Bone, inflammation and the bone marrow niche in chronic kidney disease: what do we know?

Bone, inflammation and the bone marrow niche in chronic kidney disease: what do we know? Abstract Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone–vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease–mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases. atherosclerosis, bone marrow niche, chronic kidney disease, CKD-MBD, FGF23, inflammation, PTH, renal osteodystrophy, vitamin D INTRODUCTION The recognition in recent years of the embryonic origin of bone cells (osteoclasts from haematopoietic stem/progenitor cells or HSPCs, and osteoblasts from mesenchymal stem cells or MSCs) and of the hormone-like properties of a number of ‘non-collagenous bone proteins’ confers on bone the potential for systemic extraskeletal effects [1]. In addition, the clinical effects of chronic inflammation in various systemic diseases has increasingly been recognized. Specifically, the mild chronic increase in blood and tissues of an ever-growing number of cytokines is associated with worse clinical outcomes [2]. Another recent discovery is the osteoblastic niche, the functional unit where stem cells, precursors of both haematopoietic and bone cell lineages (respectively HSPCs and MSCs), share a common environment. In this niche, these cells exchange signals that modify their fate in terms of differentiation towards immune-competent haematopoietic elements (among which osteoclasts are now included) and bone-forming cells (i.e. osteoblasts and osteocytes). There is evidence that HSPCs and MSCs share functional integrations of potential clinical relevance [3]. The aim of this review is to highlight the emerging potential links between bone, chronic inflammation and the bone marrow (BM) niche, in particular in chronic kidney disease (CKD) patients. These patients are special because they suffer a specific type of metabolic bone disease and low-grade chronic inflammation that can affect, in still underappreciated ways, the function of the osteoblastic niche; dysfunction of the latter has recently been recognized for the first time in diabetes [4]. BONE, INTER-ORGAN COMMUNICATIONS AND CKD Until recently, bone was perceived as the repository of ions—mainly calcium (Ca) and phosphate (P)—whose movement into and out of bone was regulated by parathyroid hormone (PTH) and active vitamin D through actions on osteoblasts and osteoclasts. This view changed with the discovery that osteocytes, previously thought to be inactive, in fact orchestrate osteoblast and osteoclast activity, including the synthesis of proteins with hormonal or hormone-like properties. Accordingly, bone is now recognized as an endocrine organ [5], and at least three bone proteins have been claimed to have potential systemic effects: osteocalcin (OC), fibroblast growth factor 23 (FGF23), and sclerostin (Sost). OC, the most abundant non-collagenous bone protein, is produced by osteoblasts during bone synthesis; however, during osteoclastic resorption OC is transformed into undercarboxylated OC (UcOC), which is freed into blood. By binding to a G protein-coupled receptor in beta pancreatic cells, circulating UcOC affects insulin sensitivity and muscle energy metabolism. Accordingly, OC is regarded as a biochemical mediator of inter-organ communication between bone and muscle energy [6]. FGF23, mainly produced by osteocytes, is a completely new player in the field of so-called CKD–mineral and bone disorders (CKD-MBD) [7]. By binding to FGF receptors, and in the presence of a co-receptor, alpha-Klotho, which is mainly produced in the kidney [8], circulating FGF23 regulates P handling and vitamin D synthesis in renal tubular cells. The FGF23/Klotho system is essential for P and vitamin D metabolism and represents the biochemical substrate of the inter-organ communication between bone and kidney, useful for better classification of some rare diseases [9]. Notably, in end-stage renal disease (ESRD) circulating FGF23 levels increase dramatically as an extreme bone response to the burden of P load and altered catabolism. This strong interaction between P and FGF23 has widened the spectrum of P toxicity to include, besides secondary hyperparathyroidism, cardiovascular disease (similarly to cholesterol) [10, 11]. In fact, higher quartiles of FGF23 have been associated with poor cardiovascular outcomes in renal [12–14] and non-renal patients [15], probably due to a direct, receptor-mediated effect of FGF23 on myocardiocytes that is capable of inducing left ventricular hypertrophy and myocardial fibrosis independently of the FGF co-receptor Klotho [16]. Further, Ca deficiency reduces circulating levels of FGF23, thus decreasing the FGF23-mediated inhibition of 1, 25(OH)2D3, which would exacerbate hypocalcaemia [17]. FGF23 synthesis in bone is regulated by a number of bone proteins with either inhibitory or stimulatory effects [18]. Therefore, FGF23 can also be regarded as an inter-organ communication factor between bone and the heart. Sost, produced by osteocytes, is a powerful inhibitor of the canonical Wnt (wingless-type mouse mammary tumour virus integration site) pathway and, as such, is both an inhibitor of osteoblasts and osteocytes and a promoter of osteoclast activity [19]. Indeed, human inactivating mutations of the Sost gene are associated with sclerosteosis [20], while absence of mechanical load (e.g. due to inactivity or absence of gravity) increases Sost expression in bone, promoting bone resorption and osteoporosis (OP) [21]. Also, Sost stimulates FGF23 synthesis, thus exerting indirect effects on mineral metabolism [22]. Importantly, extraskeletal roles are envisaged, since Sost mRNA expression has been described [23], although not consistently [24], in calcified aortic valves of haemodialysis patients, while higher circulating levels are invariably associated with aortic valve calcification [23, 24]. Vessel wall media layer calcification, commonly identified as arteriosclerosis, is a typical finding of ageing, diabetes and CKD whose pathogenesis is now regarded as a cell-mediated active process involving osteoblast-like cells derived from vascular smooth muscle cells. Therefore, a modulator of osteoblast activity like Sost could well be involved. Hypothetically, increased tissue levels of Sost might reflect local inhibition of the osteoblast-like cell-mediated process of calcification or high circulating levels of Sost might be a marker of low bone turnover (which in turn would favour vascular calcifications). Thus, the extraskeletal effects of Sost have potential clinical implications for cardiovascular diseases and represent a new player in the bone–vascular axis. Besides UcOC, FGF23 and Sost, which can be regarded as the principal mediators of the systemic ‘CKD-MBD syndrome’ [25], other non-collagenous bone proteins like bone alkaline phosphatase [26], the Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) proteins [18], DKK-1 and activin A [27] are under investigation to elucidate links between bone disease, derangements of divalent ion metabolism, and the burden of mortality and morbidity (in particular cardiovascular) carried by CKD-MBD [25]. In summary, bone is no longer to be viewed as a lifeless framework for muscle action; rather, it is a sophisticated organ functionally connected with muscle energy metabolism, with the kidney and with the cardiovascular system (Figure 1). CKD deeply disturbs bone physiology (as reflected by changes in circulating biomarkers), impairs its mechanical competence (as reflected by an increased fracture rate) and contributes to the complex endocrinopathy now associated with worse cardiovascular outcomes. For this reason, there is growing awareness that in renal patients it is important to recognize the specific types of renal osteodystrophy (ROD) through a bone biopsy, which is not routinely performed although it is minimally invasive and is considered the diagnostic gold standard [28]. FIGURE 1 View largeDownload slide UcOC, FGF23 and Sost are the principal mediators of the systemic metabolic effects of bone. UcOC increases insulin response of target organs and is involved with energy metabolism. Klotho-dependent receptor-mediated effects of FGF23 mainly affect mineral metabolism, while Klotho-independent effects on heart and liver produce systemic effects. Sost, a major regulator of bone cells activity, may have a role in vascular calcifications. Mineral and bone disorders resulting from CKD are expected to influence these physiologic links. FIGURE 1 View largeDownload slide UcOC, FGF23 and Sost are the principal mediators of the systemic metabolic effects of bone. UcOC increases insulin response of target organs and is involved with energy metabolism. Klotho-dependent receptor-mediated effects of FGF23 mainly affect mineral metabolism, while Klotho-independent effects on heart and liver produce systemic effects. Sost, a major regulator of bone cells activity, may have a role in vascular calcifications. Mineral and bone disorders resulting from CKD are expected to influence these physiologic links. BONE AND INFLAMMATION The link between bone and inflammation is evidenced in the process of bone fracture repair, which is, in fact, a true acute inflammatory response of the innate immunity type. At the site of a fracture, bone cells and inflammatory cells are recruited, with resultant intense crosstalk between HSPC (monocyte–macrophage–osteoclast) and MSC (pre-osteoblast–osteoblast) derived cells [29]. T lymphocytes (which can stimulate osteoclastogenesis) and B cells [which can regulate the receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) axis] are also involved, with eventual increases in circulating cytokines [30]. Obviously, this healing process is the same even in the case of asymptomatic microfractures, so that pathologic increases in microfractures can turn into systemic inflammation. Upon reflection, any chronic inflammatory state can be expected to affect bone cell activity, as is illustrated by rheumatoid arthritis (RA), OP and atherosclerosis. In RA, increases in circulating inflammatory cytokines [tumour necrosis factor-alpha (TNF-α), interleukin (IL)-17, RANKL] stimulate osteoclast maturation and activity, thereby increasing bone resorption, while increases in DKK-1 and Sost inhibit bone formation [31], inducing OP. Ageing, recently regarded as ‘inflammaging’ [32], i.e. a chronic inflammatory condition, is considered to induce senile OP through similar immunologic mechanisms. Therefore, the link between bone cells and inflammatory cells is well established, as is encapsulated in the new term ‘osteoimmunology’ [33]. As for the link with CKD, a recent paper has highlighted how CKD could be regarded as a model of accelerated ageing, with resultant bone and cardiovascular disease [34]. Interestingly, according to a recent hypothesis, the link between bone and inflammation may be of evolutionary value in terrestrial animals. This hypothesis suggests that acute inflammation induces a ‘sickness behaviour’ (malaise, fatigue, anorexia, etc.) that, in the affected animals, is necessary to spare the energy required by the immune response. This adaptive behaviour relies on a complex integrated energetic-neuroendocrine-immune response that includes increased bone resorption to guarantee sufficient amounts of two vital ions like Ca and P, which a resting animal would not be able to gather. This scenario offers support for the importance of the above-mentioned link between bone and energy. Further, one can envisage that, inasmuch as the healing process is incomplete and becomes chronic, it will become maladaptive and responsible for inflammation-related osteopaenia (so-called smoldering inflammation) [35] (Figure 2). FIGURE 2 View largeDownload slide Bone fracture elicits an acute inflammatory response that is energy demanding and associated with a ‘sickness behaviour’ usually ending with complete recovery. At variance, multiple diffuse microfractures may lead to chronic subtle inflammation and to osteopaenia. FIGURE 2 View largeDownload slide Bone fracture elicits an acute inflammatory response that is energy demanding and associated with a ‘sickness behaviour’ usually ending with complete recovery. At variance, multiple diffuse microfractures may lead to chronic subtle inflammation and to osteopaenia. The link between atherosclerosis, inflammation and bone deserves special consideration. Atherosclerosis is a chronic inflammatory process in all of its stages. The effect of atherosclerosis, as an inflammatory disease, on bone metabolism and the development of OP is suggested by observations confirming that decreased bone mineral density is a good predictor of cardiovascular events and coronary disease in postmenopausal women and men >50 years [36]. Moreover, growing evidence indicates the existence of a correlation between OP and atherosclerosis regardless of age, body mass index and cardiovascular risk factors [37]. Furthermore, chronic inflammatory processes contribute to vascular calcification, and the common finding of simultaneous vascular calcification and OP in individual patients suggests that local tissue factors govern the regulation of biomineralization [38]. New terms like ‘calcification paradox’ [39] and ‘osteocardiology’ [40] are being coined to illustrate this clinical link. Vascular calcification in atherosclerosis is triggered by the response to injury caused by oxidized low-density lipoprotein (LDLox). LDLox initiates the inflammatory process, which is amplified by the exposure of adhesion molecules and by the secretion of interleukins, C-reactive protein (CRP) and bone morphogenetic proteins (BMPs) by endothelial cells and smooth muscle cells. All these processes promote increased oxidative stress and decreased calcification inhibitors, such as matrix Glutamic acid (Gla)-protein and osteopontin. Experimental evidence implies that atherosclerotic inflammatory activity has an interrelationship with osteogenic modulation. When exposed to LDLox, endothelial cells express BMPs. Additionally, TNF-α and interferon-gamma stimulate the endothelium to express OPG, which is also produced in osteoblasts and in smooth muscle cells when stimulated with proinflammatory interleukins [41]. Hyperproduction of inflammatory markers such as CRP, IL-1, IL-6 and TNF-α is directly related to the severity of atherosclerosis and the stimulation of osteoclastogenesis [42]. Monocytes and macrophages (after HSPC recruitment from BM) are the dominant type of atherosclerotic inflammatory cell infiltrates and represent more than half of all cells at the immediate site of plaque rupture. Furthermore, leakage of cytokines and leukotrienes from activated macrophages in the atherosclerotic plaque enriches the systemic proinflammatory milieu [43]. Another implicated factor is endothelium-derived nitric oxide (NO), which is reduced at the site of vascular injury. Indeed, NO inhibits platelet adherence and aggregation, suppresses vasoconstriction, reduces the adherence of leucocytes to the endothelium, and suppresses the proliferation of vascular smooth muscle cells. Therefore, a reduction in NO activity contributes to a proinflammatory and prothrombotic milieu. In CKD, an increase in the inflammatory biomarkers TNF-α, IL-6, IL-1, CRP and fibrinogen has been reported in the blood [44]. This increase is caused by several mechanisms, including reduced clearance of proinflammatory cytokines, increased local production (e.g. due to the blood–membrane contact in dialysis patients), pathologic permeability of gut to toxins (so-called leaky gut syndrome) and induction of macrophage activation by metabolic acidosis [45–47]. Monocytes and macrophages are increased in the peripheral blood of uraemic patients even when there is no clinical evidence of an active inflammatory process or an increase in the peripheral blood of other inflammatory markers, such as CRP or proinflammatory cytokines [48]. Further, in CKD the mitochondrial respiratory system is impaired, which may be both a consequence and a cause of enhanced oxidative stress. Through elevated production of reactive oxygen species (ROS), the damaged mitochondria of uraemic patients may be able to activate the NLRP3 inflammasome, a deregulated biological system newly identified in CKD-5D patients [49–52]. Increased generation of ROS in chronic renal failure can damage proteins, lipids and nucleic acids and consequently influence cell function, inhibit enzymatic activities of the cellular respiratory chain and accelerate progression of CKD [53]. Changes in oxidative and antioxidant status, which occur from the early stages of CKD, may be exacerbated by haemodialysis [54, 55]. Therefore, oxidative stress and chronic inflammation are both important players in the mechanisms underlying CKD-related accelerated atherogenesis and ageing [34]. In turn, accelerated atherogenesis will negatively affect bone metabolism (Figure 3). FIGURE 3 View largeDownload slide CKD is a chronic inflammatory state with increased circulating pro-inflammatory cytokines (IL-17, TNF-α, RANKL, BMPs, etc.) and decreased calcification inhibitors (MGP, OPN, etc.). Circulating monocytes and enhanced oxidative stress (via the NLRP3 inflammasome) accelerate atherogenesis. Local response to the injury caused by LDLox is amplified by exposure of adhesion molecules and secretion of interleukins and BMP by endothelial cells and smooth muscle cells. All these processes further increase systemic oxidative stress, decrease calcifying inhibitors and promote vessel wall calcification. ROD, by interfering with BM niche function, is expected to contribute to this systemic microinflammatory burden that accelerates atherosclerosis, vessel calcification and osteopaenia. FIGURE 3 View largeDownload slide CKD is a chronic inflammatory state with increased circulating pro-inflammatory cytokines (IL-17, TNF-α, RANKL, BMPs, etc.) and decreased calcification inhibitors (MGP, OPN, etc.). Circulating monocytes and enhanced oxidative stress (via the NLRP3 inflammasome) accelerate atherogenesis. Local response to the injury caused by LDLox is amplified by exposure of adhesion molecules and secretion of interleukins and BMP by endothelial cells and smooth muscle cells. All these processes further increase systemic oxidative stress, decrease calcifying inhibitors and promote vessel wall calcification. ROD, by interfering with BM niche function, is expected to contribute to this systemic microinflammatory burden that accelerates atherosclerosis, vessel calcification and osteopaenia. THE BM NICHE: WHERE BONE AND MARROW MEET Bone is the chest for BM cells and the place where the egress of stem cells, including those already committed towards some specific lineages, is orchestrated [56]. The transfer of HSPCs out of the BM to the circulation requires the integrity of bone microarchitecture, within which is contained the BM functional unit: the niche. A niche is defined as a specialized microenvironment of the BM, specific for each cell lineage, that hosts and modulates HSPC renewal and egress into the bloodstream. Inside the niche, a complicated network of hormones, soluble mediators and surface cell receptors regulates the HSPC number, fate and location [57]. The niche is perivascular and located within the trabecular bone and is settled by osteoblastic cells, endothelial cells and perivascular MSCs that interact closely with each other [57, 58]. The BM niche consists of two major elements. The first is the osteoblastic niche, where cells of the osteoblastic lineage are key modulators of HSPCs, keeping them quiescent for the purposes of maintenance and self-renewal. The second element is the vascular niche, composed of vascular sinuses, lining endothelial cells, CXCL12-abundant reticular (CAR) cells, sympathetic neurons and HSPCs. Each HSPC evolves inside a specialized and specific niche [57]. Egress of HSPCs out of the BM and into the bloodstream is known as ‘mobilization’ and is coupled with HSPC ‘homing’. Homing is a set of complex pathways that modulate the mobilization of HSPCs towards both peripheral BM niches and peripheral tissues [59]. The niche composition and function ultimately depends on the activity of the bone cells since most HSPCs are found in the trabecular bone, suggesting that the function of the niche (mobilization and homing) may also be regulated by factors involved in bone remodelling [57, 58, 60]. A high number of osteoblasts raises the stem cell pool size and adherence in the niche, whereas an increase in osteoclasts degrades the niche and promotes the egress of HSPCs [61]. These processes are physiologically carried by the joint effect of PTH and inflammatory cytokines. PTH plays the role of pivotal director of the niche through activation of PTH/PTHrP receptors (PPRs), leading to HSPC expansion. Following PPR activation, osteoblastic cells produce high levels of the Notch ligand, jagged-1, which elicits an increase in the number of HSPCs [58, 62, 63]. Furthermore, in osteoblasts PTH upregulates both granulocyte colony-stimulating factor (GCSF), which in turn regulates the expression of inflammatory cytokines (IL-6 and IL-11) and CXCL12. CXCL12 is the hinge chemokine involved in the mobilization and homing processes as its interaction with the homing receptor CXCR-4, expressed on many progenitors, is the most important pathway for retention of HSPCs within the BM as well as for their mobilization. GCSF depletes osteoblasts and reduces CXCL12 expression in both osteoblasts and CAR cells, so promoting mobilization of HSPCs into the vascular sinuses [57, 58, 64]. No less relevant, within the BM niche, is the role of proinflammatory cytokines, which maintain the HSPC pool by tuning size, cell lineage, distribution and phenotype [65]. Inflammatory cytokines also affect the phenotype of BM macrophages (also called osteal macrophages): this process is known as macrophage polarization. Osteal macrophages are involved in bone repair and remodelling by regulating the crosstalk between osteoclasts and osteoblasts [66, 67]. Besides PTH, other factors involved in bone remodelling, such as FGF23/klotho, Wnt inhibitors, vitamin D, vitamin D receptor and Ca sensing receptor (CaSR), are able to influence the activity of the BM niche and the HSPC fate [9, 22, 68–70]. Moreover, MSCs give rise to osteoblasts, and their differentiation is stimulated by 1, 25(OH)2D. In addition to being targets of 1, 25(OH)2D, MSCs can synthesize it [71, 72]. Normal CaSR expression on HSPCs is an absolute requirement for their lodging in the endosteal niche of the BM [73]. Given these tight morphological and functional links, any pathological condition able to induce an imbalance in bone remodelling and a derangement in cell signaling may disrupt both the bone microarchitecture and the BM niche function and consequently the HSPC traffic [74]. All these findings are new features of the complex scenario of the bone–vascular axis. In fact, HSPCs and the precursors of cardiovascular cells may also be resident in the vascular or valvular wall or be part of the uninterrupted flow of HSPCs ensuring adequate cell renewal and contributing physiologically to vascular health [75, 76] (Figure 4). FIGURE 4 View largeDownload slide The fate of HSPCs out of the BM physiologically reflects the joined action of bone remodelling and inflammatory cytokines. PTH, by acting on osteoblasts both directly and indirectly (through JAG 1, IL-6 and GCSF), is pivotal director of HSPCs ‘mobilization’ and ‘homing’ into the bloodstream. Other factors involved with bone metabolism like FGF23, calcitriol, their receptors and the Ca-sensing receptor are relevant regulators of BM niche function. Their derangements in CKD, together with the resulting damage in terms of bone turnover and microarchitecture, are most likely responsible for BM niche dysfunction. FIGURE 4 View largeDownload slide The fate of HSPCs out of the BM physiologically reflects the joined action of bone remodelling and inflammatory cytokines. PTH, by acting on osteoblasts both directly and indirectly (through JAG 1, IL-6 and GCSF), is pivotal director of HSPCs ‘mobilization’ and ‘homing’ into the bloodstream. Other factors involved with bone metabolism like FGF23, calcitriol, their receptors and the Ca-sensing receptor are relevant regulators of BM niche function. Their derangements in CKD, together with the resulting damage in terms of bone turnover and microarchitecture, are most likely responsible for BM niche dysfunction. Several chronic diseases such as obesity, atherosclerosis, diabetes and CKD display a unique proinflammatory milieu that, along with a cluster of metabolic derangements and oxidative stress factors, may impair mobilization and homing, thereby inducing shortage and functional impairment of HSPCs, shifting the progenitor cell phenotype and ultimately influencing pathological processes such as atherosclerosis and vascular calcification. Diabetes is characterized by a broad derangement of the BM niche, with an expanded pool of quiescent HSPCs as well as a reduced number of osteoblasts slightly expressing CXCL12 and unchanged CXCL12 expression in CAR cells, resulting in decreased mobilization of haematopoietic stem cells [4]. These changes are acknowledged to be driven by chronic inflammation, stimulation of innate immunity receptors, and an increase in proinflammatory osteal macrophages [4, 77, 78]. This novel type of diabetic complication, termed ‘stem cell mobilopathy’, is the pathway via which diabetes accelerates atherosclerosis; it does this by inducing a shortage of vascular regenerative cells and by shifting the differentiation of BM progenitor cells to pro-calcific [77]. In CKD patients the uraemic inflammatory burden is enhanced by the frequent coexistence of diabetes, atherosclerosis and ageing [34]. In addition, in CKD patients, inflammation is triggered by specific pathways related to the CKD-MBD syndrome. Besides PTH, FGF23 can directly bind and activate FGFR4 and calcineurin/NFAT signaling in hepatocytes in the absence of its classic co-receptor alpha-Klotho, leading to increased expression and secretion of inflammatory cytokines (Figure 1). The relationship between FGF23 and inflammation seems to be bidirectional since inflammation increases FGF23 transcription in osteocytes. However, whether FGF23 stimulates inflammatory cytokine expression by other target cells such as adipocytes and osteoblasts is a matter of discussion [79]. FGF23 may influence the bone microarchitecture by directly tuning bone remodelling. FGF23, through a soluble Klotho/MAPK-mediated process involving Dkk1 expression, inhibits the osteoblastic Wnt pathway, so contributing to bone loss in CKD [69]. Moreover, both human pre-osteoclasts and mature osteoclasts express FGFR1 at all stages of differentiation, and FGF23 displays biphasic effects on human osteoclasts, with inhibition of osteoclast differentiation at the early stages of maturation and stimulation of activity at later stages [80]. CKD-related inflammation and bone mineral disorders could affect the complex balance within the BM niche, thus deranging the mobilization and homing of HSPCs and fostering the development of cell subsets expressing an osteogenic phenotype. This latter finding may represent a common thread that links bone remodelling, the BM niche and vascular calcification in chronic renal failure. Cells with an osteogenic phenotype may originate from vascular wall-resident MSCs, transdifferentiated mature or circulating vascular smooth muscle cells, or circulating calcifying cells (CCCs) [75, 81]. CCCs comprise several osteogenic cell subsets that express different but interrelated phenotypes, share a common origin from BM progenitor cells, and are able to promote intimal calcification. Regardless of the type of BM progenitor cell, CCCs are defined by the expression of OC and bone alkaline phosphatase. Their pool includes circulating (mesenchymal) osteoprogenitor cells, circulating calcifying endothelial progenitor cells (EPCs) and myeloid calcifying cells (MCCs) [82]. EPCs have been associated with coronary artery disease, calcific aortic stenosis, OP, diabetes and ESRD [72, 83–85]. MCCs belong to the myeloid lineage (monocytes–macrophages) and have been found to be significantly increased in the presence of either cardiovascular disease or diabetes. In addition, MCC numbers are higher in diabetic versus non-diabetic patients regardless of the coexistence of cardiovascular disease, and they are also increased in the BM and atherosclerotic plaques [86]. BONE, INFLAMMATION AND THE BM NICHE IN CKD: FINAL CONSIDERATIONS The role of BM niche impairment in vascular disease in the setting of diabetes and atherosclerosis has been assessed and such impairment is also considered to be the first step in the process leading to the appearance of CCCs. This is undoubtedly the most intriguing, though still relatively uncharted area in the multifaceted scenario of the bone–vascular axis. The discovery of BM niche impairment in vascular disease is particularly important considering that the derangement of the bone–vascular axis is amplified by ageing and by CKD, diabetes and atherosclerosis, the incidence of which is constantly rising in the general population. It is possible to speculate that inflammation is the shared pathogenetic link, also bearing in mind the possible coexistence of diabetes, atherosclerosis and CKD, and the potential effects on bone remodelling and thus on BM niche function. Studies on impairment of the BM niche in CKD are still at an early stage. This is all the more surprising if we consider the crucial role that PTH, CaSR, FGF23, vitamin D, inflammatory cytokines and bone cells are acknowledged to play in regulating the expansion, mobilization and homing of HSPCs. The inflammatory burden and the impairment of bone remodelling inherent to the CKD-MBD syndrome most likely compromise the renewal of HSPCs and the provision of cell progenitors to vascular tissues, as well as promoting the development of cell subsets that express an osteogenic phenotype and thus probably affect the process of vascular calcification. Overall, like diabetes, CKD is a potential cause of BM niche dysfunction or mobilopathy and this urgently needs to be appreciated. Indeed, the metabolic derangements of mineral metabolism and the chronic inflammatory burden of renal insufficiency can predictably affect the function of the BM niche. Similarly, the different types of ROD (e.g. high- or low-turnover bone disease with resulting differences in bone cell numbers and activity) most probably impact the BM niche. Therefore, assessment of BM niche function in CKD patients could be important for the discovery of new pathways in the complex metabolic disturbance of uraemia and its heavy burden of morbidity and mortality. CONFLICT OF INTEREST STATEMENT None declared. The results presented in this article have not been published previously in whole or part, except in abstract format. REFERENCES 1 Vervloet M , Massy Z , Brandenburg V et al. Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders . Lancet Diabetes Endocrinol 2014 ; 2 : 427 – 436 Google Scholar CrossRef Search ADS PubMed 2 Tousoulis D , Economou E , Oikonomou E et al. The role and predictive value of cytokines in atherosclerosis and coronary artery disease . Curr Med Chem 2015 ; 22 : 2636 – 2650 Google Scholar CrossRef Search ADS PubMed 3 Reagan M , Rosen C. Navigating the bone marrow niche: translational insights and cancer-driven dysfunction . 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Exp Diabetes Res 2012 ; 2012 : 1 85 Gössl M , Mödder U , Atkinson E et al. Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis . J Am Coll Cardiol 2008 ; 33 : 1314 – 1325 Google Scholar CrossRef Search ADS 86 Fadini G , Albiero M , Menegazzo L et al. Widespread increase in myeloid calcifying cells contributes to ectopic vascular calcification in type 2 diabetes . Circ Res 2011 ; 108 : 1112 – 1121 Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nephrology Dialysis Transplantation Oxford University Press

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Abstract

Abstract Recent improvements in our understanding of physiology have altered the way in which bone is perceived: no longer is it considered as simply the repository of divalent ions, but rather as a sophisticated endocrine organ with potential extraskeletal effects. Indeed, a number of pathologic conditions involving bone in different ways can now be reconsidered from a bone-centred perspective. For example, in metabolic bone diseases like osteoporosis (OP) and renal osteodystrophy (ROD), the association with a worse cardiovascular outcome can be tentatively explained by the possible derangements of three recently discovered bone hormones (osteocalcin, fibroblast growth factor 23 and sclerostin) and a bone-specific enzyme (alkaline phosphatase). Further, in recent years the close link between bone and inflammation has been better appreciated and a wide range of chronic inflammatory states (from rheumatoid arthritis to ageing) are being explored to discover the biochemical changes that ultimately lead to bone loss and OP. Also, it has been acknowledged that the concept of the bone–vascular axis may explain, for example, the relationship between bone metabolism and vessel wall diseases like atherosclerosis and arteriosclerosis, with potential involvement of a number of cytokines and metabolic pathways. A very important discovery in bone physiology is the bone marrow (BM) niche, the functional unit where stem cells interact, exchanging signals that impact on their fate as bone-forming cells or immune-competent haematopoietic elements. This new element of bone physiology has been recognized to be dysfunctional in diabetes (so-called diabetic mobilopathy), with possible clinical implications. In our opinion, ROD, the metabolic bone disease of renal patients, will in the future probably be identified as a cause of BM niche dysfunction. An integrated view of bone, which includes the BM niche, now seems necessary in order to understand the complex clinical entity of chronic kidney disease–mineral and bone disorders and its cardiovascular burden. Bone is thus becoming a recurrently considered paradigm for different inter-organ communications that needs to be considered in patients with complex diseases. atherosclerosis, bone marrow niche, chronic kidney disease, CKD-MBD, FGF23, inflammation, PTH, renal osteodystrophy, vitamin D INTRODUCTION The recognition in recent years of the embryonic origin of bone cells (osteoclasts from haematopoietic stem/progenitor cells or HSPCs, and osteoblasts from mesenchymal stem cells or MSCs) and of the hormone-like properties of a number of ‘non-collagenous bone proteins’ confers on bone the potential for systemic extraskeletal effects [1]. In addition, the clinical effects of chronic inflammation in various systemic diseases has increasingly been recognized. Specifically, the mild chronic increase in blood and tissues of an ever-growing number of cytokines is associated with worse clinical outcomes [2]. Another recent discovery is the osteoblastic niche, the functional unit where stem cells, precursors of both haematopoietic and bone cell lineages (respectively HSPCs and MSCs), share a common environment. In this niche, these cells exchange signals that modify their fate in terms of differentiation towards immune-competent haematopoietic elements (among which osteoclasts are now included) and bone-forming cells (i.e. osteoblasts and osteocytes). There is evidence that HSPCs and MSCs share functional integrations of potential clinical relevance [3]. The aim of this review is to highlight the emerging potential links between bone, chronic inflammation and the bone marrow (BM) niche, in particular in chronic kidney disease (CKD) patients. These patients are special because they suffer a specific type of metabolic bone disease and low-grade chronic inflammation that can affect, in still underappreciated ways, the function of the osteoblastic niche; dysfunction of the latter has recently been recognized for the first time in diabetes [4]. BONE, INTER-ORGAN COMMUNICATIONS AND CKD Until recently, bone was perceived as the repository of ions—mainly calcium (Ca) and phosphate (P)—whose movement into and out of bone was regulated by parathyroid hormone (PTH) and active vitamin D through actions on osteoblasts and osteoclasts. This view changed with the discovery that osteocytes, previously thought to be inactive, in fact orchestrate osteoblast and osteoclast activity, including the synthesis of proteins with hormonal or hormone-like properties. Accordingly, bone is now recognized as an endocrine organ [5], and at least three bone proteins have been claimed to have potential systemic effects: osteocalcin (OC), fibroblast growth factor 23 (FGF23), and sclerostin (Sost). OC, the most abundant non-collagenous bone protein, is produced by osteoblasts during bone synthesis; however, during osteoclastic resorption OC is transformed into undercarboxylated OC (UcOC), which is freed into blood. By binding to a G protein-coupled receptor in beta pancreatic cells, circulating UcOC affects insulin sensitivity and muscle energy metabolism. Accordingly, OC is regarded as a biochemical mediator of inter-organ communication between bone and muscle energy [6]. FGF23, mainly produced by osteocytes, is a completely new player in the field of so-called CKD–mineral and bone disorders (CKD-MBD) [7]. By binding to FGF receptors, and in the presence of a co-receptor, alpha-Klotho, which is mainly produced in the kidney [8], circulating FGF23 regulates P handling and vitamin D synthesis in renal tubular cells. The FGF23/Klotho system is essential for P and vitamin D metabolism and represents the biochemical substrate of the inter-organ communication between bone and kidney, useful for better classification of some rare diseases [9]. Notably, in end-stage renal disease (ESRD) circulating FGF23 levels increase dramatically as an extreme bone response to the burden of P load and altered catabolism. This strong interaction between P and FGF23 has widened the spectrum of P toxicity to include, besides secondary hyperparathyroidism, cardiovascular disease (similarly to cholesterol) [10, 11]. In fact, higher quartiles of FGF23 have been associated with poor cardiovascular outcomes in renal [12–14] and non-renal patients [15], probably due to a direct, receptor-mediated effect of FGF23 on myocardiocytes that is capable of inducing left ventricular hypertrophy and myocardial fibrosis independently of the FGF co-receptor Klotho [16]. Further, Ca deficiency reduces circulating levels of FGF23, thus decreasing the FGF23-mediated inhibition of 1, 25(OH)2D3, which would exacerbate hypocalcaemia [17]. FGF23 synthesis in bone is regulated by a number of bone proteins with either inhibitory or stimulatory effects [18]. Therefore, FGF23 can also be regarded as an inter-organ communication factor between bone and the heart. Sost, produced by osteocytes, is a powerful inhibitor of the canonical Wnt (wingless-type mouse mammary tumour virus integration site) pathway and, as such, is both an inhibitor of osteoblasts and osteocytes and a promoter of osteoclast activity [19]. Indeed, human inactivating mutations of the Sost gene are associated with sclerosteosis [20], while absence of mechanical load (e.g. due to inactivity or absence of gravity) increases Sost expression in bone, promoting bone resorption and osteoporosis (OP) [21]. Also, Sost stimulates FGF23 synthesis, thus exerting indirect effects on mineral metabolism [22]. Importantly, extraskeletal roles are envisaged, since Sost mRNA expression has been described [23], although not consistently [24], in calcified aortic valves of haemodialysis patients, while higher circulating levels are invariably associated with aortic valve calcification [23, 24]. Vessel wall media layer calcification, commonly identified as arteriosclerosis, is a typical finding of ageing, diabetes and CKD whose pathogenesis is now regarded as a cell-mediated active process involving osteoblast-like cells derived from vascular smooth muscle cells. Therefore, a modulator of osteoblast activity like Sost could well be involved. Hypothetically, increased tissue levels of Sost might reflect local inhibition of the osteoblast-like cell-mediated process of calcification or high circulating levels of Sost might be a marker of low bone turnover (which in turn would favour vascular calcifications). Thus, the extraskeletal effects of Sost have potential clinical implications for cardiovascular diseases and represent a new player in the bone–vascular axis. Besides UcOC, FGF23 and Sost, which can be regarded as the principal mediators of the systemic ‘CKD-MBD syndrome’ [25], other non-collagenous bone proteins like bone alkaline phosphatase [26], the Small Integrin-Binding Ligand, N-linked Glycoprotein (SIBLING) proteins [18], DKK-1 and activin A [27] are under investigation to elucidate links between bone disease, derangements of divalent ion metabolism, and the burden of mortality and morbidity (in particular cardiovascular) carried by CKD-MBD [25]. In summary, bone is no longer to be viewed as a lifeless framework for muscle action; rather, it is a sophisticated organ functionally connected with muscle energy metabolism, with the kidney and with the cardiovascular system (Figure 1). CKD deeply disturbs bone physiology (as reflected by changes in circulating biomarkers), impairs its mechanical competence (as reflected by an increased fracture rate) and contributes to the complex endocrinopathy now associated with worse cardiovascular outcomes. For this reason, there is growing awareness that in renal patients it is important to recognize the specific types of renal osteodystrophy (ROD) through a bone biopsy, which is not routinely performed although it is minimally invasive and is considered the diagnostic gold standard [28]. FIGURE 1 View largeDownload slide UcOC, FGF23 and Sost are the principal mediators of the systemic metabolic effects of bone. UcOC increases insulin response of target organs and is involved with energy metabolism. Klotho-dependent receptor-mediated effects of FGF23 mainly affect mineral metabolism, while Klotho-independent effects on heart and liver produce systemic effects. Sost, a major regulator of bone cells activity, may have a role in vascular calcifications. Mineral and bone disorders resulting from CKD are expected to influence these physiologic links. FIGURE 1 View largeDownload slide UcOC, FGF23 and Sost are the principal mediators of the systemic metabolic effects of bone. UcOC increases insulin response of target organs and is involved with energy metabolism. Klotho-dependent receptor-mediated effects of FGF23 mainly affect mineral metabolism, while Klotho-independent effects on heart and liver produce systemic effects. Sost, a major regulator of bone cells activity, may have a role in vascular calcifications. Mineral and bone disorders resulting from CKD are expected to influence these physiologic links. BONE AND INFLAMMATION The link between bone and inflammation is evidenced in the process of bone fracture repair, which is, in fact, a true acute inflammatory response of the innate immunity type. At the site of a fracture, bone cells and inflammatory cells are recruited, with resultant intense crosstalk between HSPC (monocyte–macrophage–osteoclast) and MSC (pre-osteoblast–osteoblast) derived cells [29]. T lymphocytes (which can stimulate osteoclastogenesis) and B cells [which can regulate the receptor activator of nuclear factor κB (RANK)/receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) axis] are also involved, with eventual increases in circulating cytokines [30]. Obviously, this healing process is the same even in the case of asymptomatic microfractures, so that pathologic increases in microfractures can turn into systemic inflammation. Upon reflection, any chronic inflammatory state can be expected to affect bone cell activity, as is illustrated by rheumatoid arthritis (RA), OP and atherosclerosis. In RA, increases in circulating inflammatory cytokines [tumour necrosis factor-alpha (TNF-α), interleukin (IL)-17, RANKL] stimulate osteoclast maturation and activity, thereby increasing bone resorption, while increases in DKK-1 and Sost inhibit bone formation [31], inducing OP. Ageing, recently regarded as ‘inflammaging’ [32], i.e. a chronic inflammatory condition, is considered to induce senile OP through similar immunologic mechanisms. Therefore, the link between bone cells and inflammatory cells is well established, as is encapsulated in the new term ‘osteoimmunology’ [33]. As for the link with CKD, a recent paper has highlighted how CKD could be regarded as a model of accelerated ageing, with resultant bone and cardiovascular disease [34]. Interestingly, according to a recent hypothesis, the link between bone and inflammation may be of evolutionary value in terrestrial animals. This hypothesis suggests that acute inflammation induces a ‘sickness behaviour’ (malaise, fatigue, anorexia, etc.) that, in the affected animals, is necessary to spare the energy required by the immune response. This adaptive behaviour relies on a complex integrated energetic-neuroendocrine-immune response that includes increased bone resorption to guarantee sufficient amounts of two vital ions like Ca and P, which a resting animal would not be able to gather. This scenario offers support for the importance of the above-mentioned link between bone and energy. Further, one can envisage that, inasmuch as the healing process is incomplete and becomes chronic, it will become maladaptive and responsible for inflammation-related osteopaenia (so-called smoldering inflammation) [35] (Figure 2). FIGURE 2 View largeDownload slide Bone fracture elicits an acute inflammatory response that is energy demanding and associated with a ‘sickness behaviour’ usually ending with complete recovery. At variance, multiple diffuse microfractures may lead to chronic subtle inflammation and to osteopaenia. FIGURE 2 View largeDownload slide Bone fracture elicits an acute inflammatory response that is energy demanding and associated with a ‘sickness behaviour’ usually ending with complete recovery. At variance, multiple diffuse microfractures may lead to chronic subtle inflammation and to osteopaenia. The link between atherosclerosis, inflammation and bone deserves special consideration. Atherosclerosis is a chronic inflammatory process in all of its stages. The effect of atherosclerosis, as an inflammatory disease, on bone metabolism and the development of OP is suggested by observations confirming that decreased bone mineral density is a good predictor of cardiovascular events and coronary disease in postmenopausal women and men >50 years [36]. Moreover, growing evidence indicates the existence of a correlation between OP and atherosclerosis regardless of age, body mass index and cardiovascular risk factors [37]. Furthermore, chronic inflammatory processes contribute to vascular calcification, and the common finding of simultaneous vascular calcification and OP in individual patients suggests that local tissue factors govern the regulation of biomineralization [38]. New terms like ‘calcification paradox’ [39] and ‘osteocardiology’ [40] are being coined to illustrate this clinical link. Vascular calcification in atherosclerosis is triggered by the response to injury caused by oxidized low-density lipoprotein (LDLox). LDLox initiates the inflammatory process, which is amplified by the exposure of adhesion molecules and by the secretion of interleukins, C-reactive protein (CRP) and bone morphogenetic proteins (BMPs) by endothelial cells and smooth muscle cells. All these processes promote increased oxidative stress and decreased calcification inhibitors, such as matrix Glutamic acid (Gla)-protein and osteopontin. Experimental evidence implies that atherosclerotic inflammatory activity has an interrelationship with osteogenic modulation. When exposed to LDLox, endothelial cells express BMPs. Additionally, TNF-α and interferon-gamma stimulate the endothelium to express OPG, which is also produced in osteoblasts and in smooth muscle cells when stimulated with proinflammatory interleukins [41]. Hyperproduction of inflammatory markers such as CRP, IL-1, IL-6 and TNF-α is directly related to the severity of atherosclerosis and the stimulation of osteoclastogenesis [42]. Monocytes and macrophages (after HSPC recruitment from BM) are the dominant type of atherosclerotic inflammatory cell infiltrates and represent more than half of all cells at the immediate site of plaque rupture. Furthermore, leakage of cytokines and leukotrienes from activated macrophages in the atherosclerotic plaque enriches the systemic proinflammatory milieu [43]. Another implicated factor is endothelium-derived nitric oxide (NO), which is reduced at the site of vascular injury. Indeed, NO inhibits platelet adherence and aggregation, suppresses vasoconstriction, reduces the adherence of leucocytes to the endothelium, and suppresses the proliferation of vascular smooth muscle cells. Therefore, a reduction in NO activity contributes to a proinflammatory and prothrombotic milieu. In CKD, an increase in the inflammatory biomarkers TNF-α, IL-6, IL-1, CRP and fibrinogen has been reported in the blood [44]. This increase is caused by several mechanisms, including reduced clearance of proinflammatory cytokines, increased local production (e.g. due to the blood–membrane contact in dialysis patients), pathologic permeability of gut to toxins (so-called leaky gut syndrome) and induction of macrophage activation by metabolic acidosis [45–47]. Monocytes and macrophages are increased in the peripheral blood of uraemic patients even when there is no clinical evidence of an active inflammatory process or an increase in the peripheral blood of other inflammatory markers, such as CRP or proinflammatory cytokines [48]. Further, in CKD the mitochondrial respiratory system is impaired, which may be both a consequence and a cause of enhanced oxidative stress. Through elevated production of reactive oxygen species (ROS), the damaged mitochondria of uraemic patients may be able to activate the NLRP3 inflammasome, a deregulated biological system newly identified in CKD-5D patients [49–52]. Increased generation of ROS in chronic renal failure can damage proteins, lipids and nucleic acids and consequently influence cell function, inhibit enzymatic activities of the cellular respiratory chain and accelerate progression of CKD [53]. Changes in oxidative and antioxidant status, which occur from the early stages of CKD, may be exacerbated by haemodialysis [54, 55]. Therefore, oxidative stress and chronic inflammation are both important players in the mechanisms underlying CKD-related accelerated atherogenesis and ageing [34]. In turn, accelerated atherogenesis will negatively affect bone metabolism (Figure 3). FIGURE 3 View largeDownload slide CKD is a chronic inflammatory state with increased circulating pro-inflammatory cytokines (IL-17, TNF-α, RANKL, BMPs, etc.) and decreased calcification inhibitors (MGP, OPN, etc.). Circulating monocytes and enhanced oxidative stress (via the NLRP3 inflammasome) accelerate atherogenesis. Local response to the injury caused by LDLox is amplified by exposure of adhesion molecules and secretion of interleukins and BMP by endothelial cells and smooth muscle cells. All these processes further increase systemic oxidative stress, decrease calcifying inhibitors and promote vessel wall calcification. ROD, by interfering with BM niche function, is expected to contribute to this systemic microinflammatory burden that accelerates atherosclerosis, vessel calcification and osteopaenia. FIGURE 3 View largeDownload slide CKD is a chronic inflammatory state with increased circulating pro-inflammatory cytokines (IL-17, TNF-α, RANKL, BMPs, etc.) and decreased calcification inhibitors (MGP, OPN, etc.). Circulating monocytes and enhanced oxidative stress (via the NLRP3 inflammasome) accelerate atherogenesis. Local response to the injury caused by LDLox is amplified by exposure of adhesion molecules and secretion of interleukins and BMP by endothelial cells and smooth muscle cells. All these processes further increase systemic oxidative stress, decrease calcifying inhibitors and promote vessel wall calcification. ROD, by interfering with BM niche function, is expected to contribute to this systemic microinflammatory burden that accelerates atherosclerosis, vessel calcification and osteopaenia. THE BM NICHE: WHERE BONE AND MARROW MEET Bone is the chest for BM cells and the place where the egress of stem cells, including those already committed towards some specific lineages, is orchestrated [56]. The transfer of HSPCs out of the BM to the circulation requires the integrity of bone microarchitecture, within which is contained the BM functional unit: the niche. A niche is defined as a specialized microenvironment of the BM, specific for each cell lineage, that hosts and modulates HSPC renewal and egress into the bloodstream. Inside the niche, a complicated network of hormones, soluble mediators and surface cell receptors regulates the HSPC number, fate and location [57]. The niche is perivascular and located within the trabecular bone and is settled by osteoblastic cells, endothelial cells and perivascular MSCs that interact closely with each other [57, 58]. The BM niche consists of two major elements. The first is the osteoblastic niche, where cells of the osteoblastic lineage are key modulators of HSPCs, keeping them quiescent for the purposes of maintenance and self-renewal. The second element is the vascular niche, composed of vascular sinuses, lining endothelial cells, CXCL12-abundant reticular (CAR) cells, sympathetic neurons and HSPCs. Each HSPC evolves inside a specialized and specific niche [57]. Egress of HSPCs out of the BM and into the bloodstream is known as ‘mobilization’ and is coupled with HSPC ‘homing’. Homing is a set of complex pathways that modulate the mobilization of HSPCs towards both peripheral BM niches and peripheral tissues [59]. The niche composition and function ultimately depends on the activity of the bone cells since most HSPCs are found in the trabecular bone, suggesting that the function of the niche (mobilization and homing) may also be regulated by factors involved in bone remodelling [57, 58, 60]. A high number of osteoblasts raises the stem cell pool size and adherence in the niche, whereas an increase in osteoclasts degrades the niche and promotes the egress of HSPCs [61]. These processes are physiologically carried by the joint effect of PTH and inflammatory cytokines. PTH plays the role of pivotal director of the niche through activation of PTH/PTHrP receptors (PPRs), leading to HSPC expansion. Following PPR activation, osteoblastic cells produce high levels of the Notch ligand, jagged-1, which elicits an increase in the number of HSPCs [58, 62, 63]. Furthermore, in osteoblasts PTH upregulates both granulocyte colony-stimulating factor (GCSF), which in turn regulates the expression of inflammatory cytokines (IL-6 and IL-11) and CXCL12. CXCL12 is the hinge chemokine involved in the mobilization and homing processes as its interaction with the homing receptor CXCR-4, expressed on many progenitors, is the most important pathway for retention of HSPCs within the BM as well as for their mobilization. GCSF depletes osteoblasts and reduces CXCL12 expression in both osteoblasts and CAR cells, so promoting mobilization of HSPCs into the vascular sinuses [57, 58, 64]. No less relevant, within the BM niche, is the role of proinflammatory cytokines, which maintain the HSPC pool by tuning size, cell lineage, distribution and phenotype [65]. Inflammatory cytokines also affect the phenotype of BM macrophages (also called osteal macrophages): this process is known as macrophage polarization. Osteal macrophages are involved in bone repair and remodelling by regulating the crosstalk between osteoclasts and osteoblasts [66, 67]. Besides PTH, other factors involved in bone remodelling, such as FGF23/klotho, Wnt inhibitors, vitamin D, vitamin D receptor and Ca sensing receptor (CaSR), are able to influence the activity of the BM niche and the HSPC fate [9, 22, 68–70]. Moreover, MSCs give rise to osteoblasts, and their differentiation is stimulated by 1, 25(OH)2D. In addition to being targets of 1, 25(OH)2D, MSCs can synthesize it [71, 72]. Normal CaSR expression on HSPCs is an absolute requirement for their lodging in the endosteal niche of the BM [73]. Given these tight morphological and functional links, any pathological condition able to induce an imbalance in bone remodelling and a derangement in cell signaling may disrupt both the bone microarchitecture and the BM niche function and consequently the HSPC traffic [74]. All these findings are new features of the complex scenario of the bone–vascular axis. In fact, HSPCs and the precursors of cardiovascular cells may also be resident in the vascular or valvular wall or be part of the uninterrupted flow of HSPCs ensuring adequate cell renewal and contributing physiologically to vascular health [75, 76] (Figure 4). FIGURE 4 View largeDownload slide The fate of HSPCs out of the BM physiologically reflects the joined action of bone remodelling and inflammatory cytokines. PTH, by acting on osteoblasts both directly and indirectly (through JAG 1, IL-6 and GCSF), is pivotal director of HSPCs ‘mobilization’ and ‘homing’ into the bloodstream. Other factors involved with bone metabolism like FGF23, calcitriol, their receptors and the Ca-sensing receptor are relevant regulators of BM niche function. Their derangements in CKD, together with the resulting damage in terms of bone turnover and microarchitecture, are most likely responsible for BM niche dysfunction. FIGURE 4 View largeDownload slide The fate of HSPCs out of the BM physiologically reflects the joined action of bone remodelling and inflammatory cytokines. PTH, by acting on osteoblasts both directly and indirectly (through JAG 1, IL-6 and GCSF), is pivotal director of HSPCs ‘mobilization’ and ‘homing’ into the bloodstream. Other factors involved with bone metabolism like FGF23, calcitriol, their receptors and the Ca-sensing receptor are relevant regulators of BM niche function. Their derangements in CKD, together with the resulting damage in terms of bone turnover and microarchitecture, are most likely responsible for BM niche dysfunction. Several chronic diseases such as obesity, atherosclerosis, diabetes and CKD display a unique proinflammatory milieu that, along with a cluster of metabolic derangements and oxidative stress factors, may impair mobilization and homing, thereby inducing shortage and functional impairment of HSPCs, shifting the progenitor cell phenotype and ultimately influencing pathological processes such as atherosclerosis and vascular calcification. Diabetes is characterized by a broad derangement of the BM niche, with an expanded pool of quiescent HSPCs as well as a reduced number of osteoblasts slightly expressing CXCL12 and unchanged CXCL12 expression in CAR cells, resulting in decreased mobilization of haematopoietic stem cells [4]. These changes are acknowledged to be driven by chronic inflammation, stimulation of innate immunity receptors, and an increase in proinflammatory osteal macrophages [4, 77, 78]. This novel type of diabetic complication, termed ‘stem cell mobilopathy’, is the pathway via which diabetes accelerates atherosclerosis; it does this by inducing a shortage of vascular regenerative cells and by shifting the differentiation of BM progenitor cells to pro-calcific [77]. In CKD patients the uraemic inflammatory burden is enhanced by the frequent coexistence of diabetes, atherosclerosis and ageing [34]. In addition, in CKD patients, inflammation is triggered by specific pathways related to the CKD-MBD syndrome. Besides PTH, FGF23 can directly bind and activate FGFR4 and calcineurin/NFAT signaling in hepatocytes in the absence of its classic co-receptor alpha-Klotho, leading to increased expression and secretion of inflammatory cytokines (Figure 1). The relationship between FGF23 and inflammation seems to be bidirectional since inflammation increases FGF23 transcription in osteocytes. However, whether FGF23 stimulates inflammatory cytokine expression by other target cells such as adipocytes and osteoblasts is a matter of discussion [79]. FGF23 may influence the bone microarchitecture by directly tuning bone remodelling. FGF23, through a soluble Klotho/MAPK-mediated process involving Dkk1 expression, inhibits the osteoblastic Wnt pathway, so contributing to bone loss in CKD [69]. Moreover, both human pre-osteoclasts and mature osteoclasts express FGFR1 at all stages of differentiation, and FGF23 displays biphasic effects on human osteoclasts, with inhibition of osteoclast differentiation at the early stages of maturation and stimulation of activity at later stages [80]. CKD-related inflammation and bone mineral disorders could affect the complex balance within the BM niche, thus deranging the mobilization and homing of HSPCs and fostering the development of cell subsets expressing an osteogenic phenotype. This latter finding may represent a common thread that links bone remodelling, the BM niche and vascular calcification in chronic renal failure. Cells with an osteogenic phenotype may originate from vascular wall-resident MSCs, transdifferentiated mature or circulating vascular smooth muscle cells, or circulating calcifying cells (CCCs) [75, 81]. CCCs comprise several osteogenic cell subsets that express different but interrelated phenotypes, share a common origin from BM progenitor cells, and are able to promote intimal calcification. Regardless of the type of BM progenitor cell, CCCs are defined by the expression of OC and bone alkaline phosphatase. Their pool includes circulating (mesenchymal) osteoprogenitor cells, circulating calcifying endothelial progenitor cells (EPCs) and myeloid calcifying cells (MCCs) [82]. EPCs have been associated with coronary artery disease, calcific aortic stenosis, OP, diabetes and ESRD [72, 83–85]. MCCs belong to the myeloid lineage (monocytes–macrophages) and have been found to be significantly increased in the presence of either cardiovascular disease or diabetes. In addition, MCC numbers are higher in diabetic versus non-diabetic patients regardless of the coexistence of cardiovascular disease, and they are also increased in the BM and atherosclerotic plaques [86]. BONE, INFLAMMATION AND THE BM NICHE IN CKD: FINAL CONSIDERATIONS The role of BM niche impairment in vascular disease in the setting of diabetes and atherosclerosis has been assessed and such impairment is also considered to be the first step in the process leading to the appearance of CCCs. This is undoubtedly the most intriguing, though still relatively uncharted area in the multifaceted scenario of the bone–vascular axis. The discovery of BM niche impairment in vascular disease is particularly important considering that the derangement of the bone–vascular axis is amplified by ageing and by CKD, diabetes and atherosclerosis, the incidence of which is constantly rising in the general population. It is possible to speculate that inflammation is the shared pathogenetic link, also bearing in mind the possible coexistence of diabetes, atherosclerosis and CKD, and the potential effects on bone remodelling and thus on BM niche function. Studies on impairment of the BM niche in CKD are still at an early stage. This is all the more surprising if we consider the crucial role that PTH, CaSR, FGF23, vitamin D, inflammatory cytokines and bone cells are acknowledged to play in regulating the expansion, mobilization and homing of HSPCs. The inflammatory burden and the impairment of bone remodelling inherent to the CKD-MBD syndrome most likely compromise the renewal of HSPCs and the provision of cell progenitors to vascular tissues, as well as promoting the development of cell subsets that express an osteogenic phenotype and thus probably affect the process of vascular calcification. Overall, like diabetes, CKD is a potential cause of BM niche dysfunction or mobilopathy and this urgently needs to be appreciated. Indeed, the metabolic derangements of mineral metabolism and the chronic inflammatory burden of renal insufficiency can predictably affect the function of the BM niche. Similarly, the different types of ROD (e.g. high- or low-turnover bone disease with resulting differences in bone cell numbers and activity) most probably impact the BM niche. 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Nephrology Dialysis TransplantationOxford University Press

Published: May 4, 2018

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