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Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases

Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation:... J Mol Med (2010) 88:227–233 DOI 10.1007/s00109-009-0567-8 REVIEW Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases Jeske J. Smink & Achim Leutz Received: 7 September 2009 /Revised: 23 October 2009 /Accepted: 2 November 2009 /Published online: 27 November 2009 The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Lytic bone diseases and in particular osteoporosis Introduction are common age-related diseases characterized by enhanced bone fragility due to loss of bone density. Increasingly, Regulating bone mass, bone turnover (remodeling), and osteoporosis poses a major global health-care problem due bone integrity requires a tight coupling between the two to the growth of the elderly population. Recently, it was major bone cell types, the bone-forming osteoblasts, and found that the gene regulatory transcription factor CCAAT/ the bone-resorbing osteoclasts [1]. Maintenance of a correct enhancer binding protein beta (C/EBPβ) is involved in balance between the functions of both cell types is crucial bone metabolism. C/EBPβ occurs as different protein during the phase of skeletal development and retaining isoforms of variable amino terminal length, and regulation bone homeostasis during adulthood. Pathological bone loss of the C/EBPβ isoform ratio balance was found to represent may occur when the cross talk between osteoblasts and an important factor in osteoclast differentiation and bone osteoclasts is disturbed. This is often due to increased homeostasis. Interestingly, adjustment of the C/EBPβ iso- osteoclastic activity and diminished osteoblast activity, as form ratio by the process of translational control is observed in age-related and secondary osteoporosis or in downstream of the mammalian target of rapamycin kinase inflammation-induced (e.g., in rheumatoid arthritis) or cancer- (mTOR), a sensor of the nutritional status and a target of induced bone loss (reviewed in [2]). Although therapeutic immunosuppressive and anticancer drugs. The findings strategies to treat osteoporosis have been developed, increas- imply that modulating the process of translational control ing knowledge on the regulation of osteoclastogenesis may of C/EBPβ isoform expression could represent a novel facilitate identification of novel therapeutic targets and therapeutic approach in osteolytic bone diseases, including rational approaches. cancer and infection-induced bone loss. Recently, a novel player in the regulation of osteoclast differentiation has been identified as the transcription factor . . . . Keywords C/EBPβ MafB Osteoporosis Rapamycin CCAAT/enhancer binding protein beta (C/EBPβ)[3]. Cancer Leukemia C/EBPβ was found to affect both osteoblast activity in bone formation and osteoclast activity in bone resorption. These insights were obtained by combining studies of recombinant genetic mouse models and cell biological, pharmacological, and gene expression-profiling approaches. Briefly, the distinct C/EBPβ isoforms were found to differentially regulate expression of the downstream transcription factor : MafB that acts like a brake to restrict osteoclastic differen- J. J. Smink A. Leutz (*) Max Delbrueck Center for Molecular Medicine, tiation and osteolytic activity [4]. C/EBPβ is normally Humboldt University Berlin, Institute of Biology, expressed as two long transactivator isoforms, termed Berlin-Brandenburg Center for Regenerative Therapies, “LAP*/LAP” or as a truncated repressor, termed “LIP” Robert-Roessle-Str.10, (for the sake of simplicity, we will not discriminate between 13125 Berlin, Germany both activator isoforms, although LAP* displays additional e-mail: [email protected] 228 J Mol Med (2010) 88:227–233 epigenetic features in comparison to LAP). The balance between LAP*/LAP and LIP is adjusted by the mammalian target of rapamycin kinase (mTOR) pathway, which acts as a sensor to integrate growth and nutrient stimuli. The LAP C/EBPβ isoform enhances expression of MafB that subsequently blunts osteoclastogenesis, whereas the trun- cated LIP C/EBPβ isoform enhances osteoclastogenesis by decreasing expression of MafB [3]. C/EBPβ The transcription factor C/EBPβ belongs to the gene regulator family of the CCAAT/enhancer binding proteins, which consists of six members: α, β, δ, γ, ε, and ζ. C/EBPs are characterized by highly conserved carboxyl terminal “basic leucine zipper domains” (bZip), containing an alpha Fig. 1 Translational control and C/EBPβ isoform regulation. Growth helical basic DNA binding domain and a leucine zipper factor, hormone, nutrition, and stress signals are integrated by the coiled-coil dimerization domain. The N-terminal domains of mammalian mTOR kinase that monitors the growth and differentiation C/EBPs are more variable and only partially conserved. The status of a cell. The mTOR kinase (low activity (blue); high activity (red)) regulates the function of the translation initiation machinery. two main members C/EBPα and C/EBPβ are partially The cis-regulatory upstream open reading frame uORF in the C/EBPβ redundant during embryogenesis, and after birth, are mRNA senses the activity of the translation machinery and directs involved in cell growth, proliferation, and differentiation in initiation, leaky scanning, and reinitiation. High activity of the several tissues [5]. Both C/EBPα and C/EBPβ are encoded translation machinery directs reinitiation and production of the truncated “repressor” isoform LIP of C/EBPβ. Lowering the activity by intronless genes and are present as single messenger of the initiation machinery results in leaky scanning over the uORF RNAs (mRNAs). Nevertheless, amino terminally truncated ATG and translation initiation at the first ATG, resulting in the protein isoforms may be generated by a process known as production of the long “activator” isoform LAP. Rapamycin inhibits alternative translation initiation [6]. Thus, the protein mTOR signaling, resulting in the production of mainly the LAP isoform isoforms display different domains and exert distinct biological functions [7]. Alternative initiation of C/EBP translation is mediated by small “upstream open reading frames” (uORF) that act domains, LAP*, LAP (both are transcriptional activators), as regulatory elements to sense the activity of the and LIP (a transdominant repressor), each displaying translation machinery and to direct initiation to alternative unique functions in various cellular processes. The diversity start codons. A key signaling component of regulated of C/EBPβ’s functional properties is further increased by translational initiation is the mTOR. The activity of mTOR signaling-dependent posttranslational modifications that depends on nutritional signals, including glucose and amino regulate the biological activity and the subcellular distribu- acid availability, and it also responds to extracellular signals tion of C/EBPβ [7]. Action of C/EBPβ requires dimeriza- such as growth factors and insulin [8]. The macrolide tion through the bZip domain, either with another C/EBPβ antibiotic rapamycin specifically inhibits the mTOR kinase, molecule or through heterodimerization with any of the lowering the activity of the critical eukaryotic translation other C/EBP family members or some transcription factors initiation factor 4E (eIF4E). Low eIF4E activity abolishes with compatible bZip domains. translation reinitiation, and in the case of C/EBPβ, diminishes expression of LIP. This results in a higher LAP to LIP ratio of the C/EBPβ isoforms and alters C/EBPβ controls bone cells expression of C/EBPβ target genes (Fig. 1)[6]. C/EBPβ is involved in the differentiation of a large C/EBPβ has been suggested to act as a scaffold protein in variety of cell types, including keratinocytes, hepatocytes, the assembly of osteogenic transcription factors [9], such as mammary epithelial cells, ovarian luteal cells, adipocytes, B with Runx2 or ATF4, thereby enhancing osteoblast differ- cells, and macrophages. Moreover, C/EBPβ regulates cell entiation [10, 11]. Analyses of C/EBPβ-deficient mice survival, apoptosis, metabolism, inflammation, and tumor- confirmed a role of C/EBPβ in osteoblast differentiation igenic transformation [5, 7, 9]. C/EBPβ is expressed as and bone formation: In the absence of C/EBPβ, bone mass three different protein isoforms differing in their N-terminal is decreased [12] due to decreased osteoblast differentiation J Mol Med (2010) 88:227–233 229 and function [11]; however, this appeared to entail also produce osteoprotegerin, a decoy receptor of RANK-L, noncell autonomous effects [3, 13]. C/EBPβ deficiency thereby counteracting and fine tuning the effect of RANK-L also resulted in growth retardation during embryogenesis in osteoclastogenesis. These cytokines activate downstream [11, 14] and at postnatal stages [3], due to diminished osteoclastic transcription factors, including NFATc1, Mitf, chondrocyte differentiation [11, 14]. C/EBPβ activates the and c-Fos that affect proliferation, differentiation, and survival kip cyclin-dependent kinase inhibitor p57 in chondrocytes of osteoclasts [2, 26]. that restricts chondrocyte proliferation and stimulates the Absence of C/EBPβ or expression of only the LIP transition to hypertrophic differentiation [14]. isoform was observed to strongly enhance osteoclast Surprisingly, expression of the (repressor) LIP isoform differentiation. This suggested that the absence of LAP instead of the entire C/EBPβ gene from its endogenous would cause enhanced osteoclastogenesis, and LAP would locus in “knock-in” mouse mutants restored bone formation induce a gene whose product blocks osteoclast differenti- and rescued the growth retardation observed in C/EBPβ- ation. Such an inhibitor was identified as MafB, a deficient animals [3]. Moreover, LIP enhanced osteoblast transcription factor recently found to be involved in differentiation and function [3], possibly by acting as a osteoclastogenesis [4] and a target gene of LAP [3]. coactivator for Runx2 [10]. MafB is also a bZIP transcription factor that, however, Besides cell autonomous effects, C/EBPβ is possibly belongs to a distinct family. MafB is important in several also involved in paracrine action and the coupling between developmental processes [27] and in oncogenesis [28]. In osteoblasts and osteoclasts. C/EBPβ and its related family the hematopoietic system, the function of MafB is restricted member C/EBPδ induce IGF-I expression [15–18] that to the monocytic lineage [29]. Similarly to C/EBPβ, the represents an important anabolic factor for bone formation. expression of MafB starts at the myeloblast stage and Similar to TGFβ [19], IGF-I is released from the bone strongly increases during macrophage differentiation [29]. matrix by osteoclasts and may then stimulate osteoblasts Although not strictly required for macrophage differentia- [20]. In addition, coupling between osteoclasts and osteo- tion, absence of MafB in monocytes results in an altered blasts is thought to involve the cytokines interleukin 6 (IL- phenotype. Absence of MafB reduces F4/80 levels in 6) and tumor necrosis factor alpha (TNFα)[20] that also macrophages [30]. Upon M-CSF treatment, MafB-deficient represent targets of C/EBPβ in osteoclasts [3]. macrophages form multiple extensive cellular extrusions, often branched, known as filopodia [31], a process that also occurs in osteoclasts and that is required for cell migration C/EBPβ as a switch in osteoclast differentiation [32]. MafB directs macrophage versus osteoclast differentia- The first observations suggesting a connection between tion [4], and recently, MafB was reported to restrict M-CSF C/EBPβ and osteoporosis were made over a decade ago in receptor-induced activation of the PU.1 gene [33] that connection with the cytokine IL6. C/EBPβ, in synergy with encodes an early and essential myeloid and osteoclastic NFκB, was found to act downstream of estrogen, involving transcription factor [26]. No bone phenotype has been binding of the estrogen receptor and resulting in suppres- reported of MafB knockout mice so far, possibly due to sion of IL6 gene transcription in osteoblasts [21]. This is of their early postnatal lethality [27]. However, the MafB clinical relevance as decreased estrogen levels are one of protein interacts with and thereby attenuates the activity of the major causes of postmenopausal osteoporosis, which the osteoclastogenic transcription factors NFATc1, Mitf, results in increased IL-6 that activates osteoclasts and thus and c-Fos [4]. The long C/EBPβ isoform LAP induces bone resorption [22, 23]. Indeed, C/EBPβ-deficient mice MafB expression and thus inhibits osteoclastogenesis, show a similar general pathology as mice overexpressing whereas absence of LAP (such as in C/EBPβ-deficient IL6 [24] and with bone loss as a consequence of enhanced animals or in knockin mutants expressing only the activity of osteoclasts [3]. Macrophage defects observed in inhibitory LIP isoform) results in diminished MafB expres- C/EBPβ-deficient mice [25] were the first indication of a sion. Lack of MafB enhances the functionality of NFATc1, possible role of C/EBPβ in the bone-resorbing osteoclast, its downstream target OSCAR, and probably other factors, which shares a monocytic precursor cell with macrophages. including Mitf and c-Fos, to augment expression of In contrast to macrophages, osteoclast precursors fuse into osteoclast genes, including the cell fusion-promoting genes large polykaryons to generate mature osteoclasts that attach to DC-STAMP, ATP6v0d2, and TNFα [34]. The opposing the bone surface and resorb bone matrix. Both differentiation roles of the different C/EBPβ protein isoforms in MafB and osteolytic activity of osteoclasts requires macrophage expression suggest that the C/EBPβ isoform ratio plays a colony-stimulating factor (M-CSF) and membrane-bound fundamental role as an upstream regulator in the initiation receptor activator of NFκB ligand (RANK-L), which are both of osteoclastogenesis and connects MafB expression and osteoclastogenesis to the mTOR pathway (Fig. produced by osteoblasts and by stromal cells. Osteoblasts also 2). 230 J Mol Med (2010) 88:227–233 Fig. 2 C/EBPβ as a master switch in osteoclast differentiation. a The and TNFα (partially derived from [4, 34]). b The LIP isoform of LAP isoform of C/EBPβ induces expression of MafB. MafB binds to C/EBPβ inhibits MafB expression. As a result, MafB becomes and inactivates the osteoclastic transcription factors c-Fos, Mitf, and limiting, and lack of MafB permits access of the osteoclast NFATc1. Inactivation of these key transcription factors prevents transcription factors (often in conjunction with NFATc1 as a major osteoclast differentiation by inhibition of osteoclast target gene osteoclast transcription factor) to activate target genes and osteoclast expression of OSCAR and NFATc1, resulting in inhibition of NFATc1 differentiation target genes, including the cell fusion genes DC-STAMP, ATP6v0d2, Implications for osteolytic diseases as raloxifene, or strontium ranelate [1, 2, 35]. However, bisphosphonates inhibit the bone remodeling cycle, raising Therapies of osteoporosis concentrate on the inhibition of the need for the development of shorter-acting resorption the pathological bone resorption by osteoclasts using inhibitors, which will not affect the bone-remodeling mainly bisphosphonates, but also estrogen-like drugs such process itself too much to ensure continuous repair of Fig. 3 Dual effect of rapamycin on cancer-induced bone loss. a In this hypothetical model, several types of tumor cells with high LIP expression (breast, prostate, lung, multiple myeloma) preferentially generate osteolytic metastasis by activating osteoclasts to release tumor-promoting growth factors (e.g., TGFβ, IGF-I). This results in a continuous cycle of stimu- lation of metastatic cells and bone resorption (derived from [56]). b The vicious circle between tumor and stroma (osteoclasts) may be interrupted by drugs that impinge on translational control, such as rapamycin or its derivatives J Mol Med (2010) 88:227–233 231 microfractures and prevent additional weaknesses of the local bone loss occurs, and rapamycin was found to be skeleton [2]. Therefore, novel therapeutic strategies are beneficial due to its immunosuppressant characteristics [50, required to improve treatment strategies in osteoporosis and 51]. The observation that rapamycin also functions as an other lytic bone diseases. The findings of involvement of antiresorptive agent by modulating the C/EBPβ isoform translational control of C/EBPβ isoforms in directing ratio [3] may suggest a bipartite function [52] as tumor osteoclastogenesis may entail such novel targets for suppressor or immune suppressant and as an osteoclast therapy. Translational control is affected by the antibiotic regulator, as depicted in Fig. 3. rapamycin that specifically inhibits mTOR signaling, Rapamycin’s immunosuppressant action due to modulation resulting in a shift of the C/EBPβ isoform ratio toward of regulatory T cells might raise concerns when used for other the LAP isoform (Fig. 1). Rapamycin treatment thus favors purposes than immunosuppression, e.g., as in cancer patients LAP expression over LIP, which results in enhanced MafB or elderly with osteolytic diseases. Problems in wound healing gene activation and thus inhibition of both osteoclasto- [53] and occurrence of anemia [54] have been reported, genesis and bone resorption. Inhibition of mTOR by although no increase in infectious complications are also rapamycin inhibits osteoclastogenesis not only in mouse reported [55]. [3, 36] but also in human cells [37], suggesting that the It is interesting to note that the downstream C/EBPβ target murine model may provide disease relevant data. Impor- MafB has also been found to be deregulated in the majority of tantly, a derivative of rapamycin has already been shown to multiple myeloma cases [28]. Moreover, C/EBPβ is known inhibit bone loss in an experimental rat model, where to play a central role in inflammation. Both processes have a osteoporosis was induced by ovariectomy [37]. So far, strong impact on osteoclastogenesis and can induce patho- however, no clinical data is available concerning the impact logical bone resorption. The recent identification of the role of rapamycin on bone. Taken together, these data suggest of the C/EBPβ isoform ratio in the control of osteoclast that rapamycin could potentially serve as a therapeutic differentiation and bone resorption may link the pathology of agent in treating osteolytic diseases [38]. these lytic bone diseases to the translational control of a The mTOR signaling pathway is also important in the distinct gene regulator and may thus open new avenues for regulation of autophagy, a process recently proposed to be novel therapeutic approaches. involved in osteoclast function [39, 40]. Rapamycin The usage of rapamycin to direct translational control induces autophagy and therefore might play a role in late might have several potential benefits to treat osteolytic- osteoclastogenesis. This would be in addition to the action associated diseases, as it can attack these diseases at different of rapamycin early in osteoclast differentiation, where it levels. Rapamycin treatment, combined with restraining inhibits differentiation [3]. Autophagy was suggested to osteoclast differentiation, may have combinatorial functions decelerate aging processes [41], as also recently found for in treating osteolytic diseases. However, one has to take into rapamycin that extends the life span of aged mice [42]. This consideration that inhibition of the mTOR pathway could may suggest that dampening mTOR signaling prevents age- have adverse side effects, requiring the development of novel related disease progression, including cancer. rapamycin analogs or novel tissue-specific mTOR inhibitors Along these lines, the LIP isoform has been associated displaying less side effects. with enhanced proliferation of multiple myeloma and breast cancer and in Hodgkin and anaplastic large cell lymphoma. Acknowledgments The authors are grateful to Dr. J Tuckermann A rapamycin derivative was demonstrated to decrease (Leibnitz Institute for Age Research, Jena, Germany) for critically tumor cell proliferation by abrogating LIP expression reading the manuscript. The authors are also thankful to the members [43]. These observations further strengthen the notion that of the Leutz laboratory for helpful discussions. The authors apologize to all those authors whose work was not cited in this minireview due C/EBPβ is an important downstream target of mTOR, to space limitations. This work was supported by the Berliner affecting cell proliferation and differentiation in diverse cell Krebsgesellschaft (LEFF200708). The authors declare that they have types. Moreover, rapamycin has been shown to inhibit no competing financial interests. tumor cell metastasis in an osteosarcoma mouse model Open Access This article is distributed under the terms of the Crea- [44]. 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Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases

Smink, Jeske J.; Leutz, Achim
Journal of Molecular Medicine (Berlin, Germany) , Volume 88 (3) – Nov 27, 2009
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© The Author(s) 2009
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10.1007/s00109-009-0567-8
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J Mol Med (2010) 88:227–233 DOI 10.1007/s00109-009-0567-8 REVIEW Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases Jeske J. Smink & Achim Leutz Received: 7 September 2009 /Revised: 23 October 2009 /Accepted: 2 November 2009 /Published online: 27 November 2009 The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Lytic bone diseases and in particular osteoporosis Introduction are common age-related diseases characterized by enhanced bone fragility due to loss of bone density. Increasingly, Regulating bone mass, bone turnover (remodeling), and osteoporosis poses a major global health-care problem due bone integrity requires a tight coupling between the two to the growth of the elderly population. Recently, it was major bone cell types, the bone-forming osteoblasts, and found that the gene regulatory transcription factor CCAAT/ the bone-resorbing osteoclasts [1]. Maintenance of a correct enhancer binding protein beta (C/EBPβ) is involved in balance between the functions of both cell types is crucial bone metabolism. C/EBPβ occurs as different protein during the phase of skeletal development and retaining isoforms of variable amino terminal length, and regulation bone homeostasis during adulthood. Pathological bone loss of the C/EBPβ isoform ratio balance was found to represent may occur when the cross talk between osteoblasts and an important factor in osteoclast differentiation and bone osteoclasts is disturbed. This is often due to increased homeostasis. Interestingly, adjustment of the C/EBPβ iso- osteoclastic activity and diminished osteoblast activity, as form ratio by the process of translational control is observed in age-related and secondary osteoporosis or in downstream of the mammalian target of rapamycin kinase inflammation-induced (e.g., in rheumatoid arthritis) or cancer- (mTOR), a sensor of the nutritional status and a target of induced bone loss (reviewed in [2]). Although therapeutic immunosuppressive and anticancer drugs. The findings strategies to treat osteoporosis have been developed, increas- imply that modulating the process of translational control ing knowledge on the regulation of osteoclastogenesis may of C/EBPβ isoform expression could represent a novel facilitate identification of novel therapeutic targets and therapeutic approach in osteolytic bone diseases, including rational approaches. cancer and infection-induced bone loss. Recently, a novel player in the regulation of osteoclast differentiation has been identified as the transcription factor . . . . Keywords C/EBPβ MafB Osteoporosis Rapamycin CCAAT/enhancer binding protein beta (C/EBPβ)[3]. Cancer Leukemia C/EBPβ was found to affect both osteoblast activity in bone formation and osteoclast activity in bone resorption. These insights were obtained by combining studies of recombinant genetic mouse models and cell biological, pharmacological, and gene expression-profiling approaches. Briefly, the distinct C/EBPβ isoforms were found to differentially regulate expression of the downstream transcription factor : MafB that acts like a brake to restrict osteoclastic differen- J. J. Smink A. Leutz (*) Max Delbrueck Center for Molecular Medicine, tiation and osteolytic activity [4]. C/EBPβ is normally Humboldt University Berlin, Institute of Biology, expressed as two long transactivator isoforms, termed Berlin-Brandenburg Center for Regenerative Therapies, “LAP*/LAP” or as a truncated repressor, termed “LIP” Robert-Roessle-Str.10, (for the sake of simplicity, we will not discriminate between 13125 Berlin, Germany both activator isoforms, although LAP* displays additional e-mail: [email protected] 228 J Mol Med (2010) 88:227–233 epigenetic features in comparison to LAP). The balance between LAP*/LAP and LIP is adjusted by the mammalian target of rapamycin kinase (mTOR) pathway, which acts as a sensor to integrate growth and nutrient stimuli. The LAP C/EBPβ isoform enhances expression of MafB that subsequently blunts osteoclastogenesis, whereas the trun- cated LIP C/EBPβ isoform enhances osteoclastogenesis by decreasing expression of MafB [3]. C/EBPβ The transcription factor C/EBPβ belongs to the gene regulator family of the CCAAT/enhancer binding proteins, which consists of six members: α, β, δ, γ, ε, and ζ. C/EBPs are characterized by highly conserved carboxyl terminal “basic leucine zipper domains” (bZip), containing an alpha Fig. 1 Translational control and C/EBPβ isoform regulation. Growth helical basic DNA binding domain and a leucine zipper factor, hormone, nutrition, and stress signals are integrated by the coiled-coil dimerization domain. The N-terminal domains of mammalian mTOR kinase that monitors the growth and differentiation C/EBPs are more variable and only partially conserved. The status of a cell. The mTOR kinase (low activity (blue); high activity (red)) regulates the function of the translation initiation machinery. two main members C/EBPα and C/EBPβ are partially The cis-regulatory upstream open reading frame uORF in the C/EBPβ redundant during embryogenesis, and after birth, are mRNA senses the activity of the translation machinery and directs involved in cell growth, proliferation, and differentiation in initiation, leaky scanning, and reinitiation. High activity of the several tissues [5]. Both C/EBPα and C/EBPβ are encoded translation machinery directs reinitiation and production of the truncated “repressor” isoform LIP of C/EBPβ. Lowering the activity by intronless genes and are present as single messenger of the initiation machinery results in leaky scanning over the uORF RNAs (mRNAs). Nevertheless, amino terminally truncated ATG and translation initiation at the first ATG, resulting in the protein isoforms may be generated by a process known as production of the long “activator” isoform LAP. Rapamycin inhibits alternative translation initiation [6]. Thus, the protein mTOR signaling, resulting in the production of mainly the LAP isoform isoforms display different domains and exert distinct biological functions [7]. Alternative initiation of C/EBP translation is mediated by small “upstream open reading frames” (uORF) that act domains, LAP*, LAP (both are transcriptional activators), as regulatory elements to sense the activity of the and LIP (a transdominant repressor), each displaying translation machinery and to direct initiation to alternative unique functions in various cellular processes. The diversity start codons. A key signaling component of regulated of C/EBPβ’s functional properties is further increased by translational initiation is the mTOR. The activity of mTOR signaling-dependent posttranslational modifications that depends on nutritional signals, including glucose and amino regulate the biological activity and the subcellular distribu- acid availability, and it also responds to extracellular signals tion of C/EBPβ [7]. Action of C/EBPβ requires dimeriza- such as growth factors and insulin [8]. The macrolide tion through the bZip domain, either with another C/EBPβ antibiotic rapamycin specifically inhibits the mTOR kinase, molecule or through heterodimerization with any of the lowering the activity of the critical eukaryotic translation other C/EBP family members or some transcription factors initiation factor 4E (eIF4E). Low eIF4E activity abolishes with compatible bZip domains. translation reinitiation, and in the case of C/EBPβ, diminishes expression of LIP. This results in a higher LAP to LIP ratio of the C/EBPβ isoforms and alters C/EBPβ controls bone cells expression of C/EBPβ target genes (Fig. 1)[6]. C/EBPβ is involved in the differentiation of a large C/EBPβ has been suggested to act as a scaffold protein in variety of cell types, including keratinocytes, hepatocytes, the assembly of osteogenic transcription factors [9], such as mammary epithelial cells, ovarian luteal cells, adipocytes, B with Runx2 or ATF4, thereby enhancing osteoblast differ- cells, and macrophages. Moreover, C/EBPβ regulates cell entiation [10, 11]. Analyses of C/EBPβ-deficient mice survival, apoptosis, metabolism, inflammation, and tumor- confirmed a role of C/EBPβ in osteoblast differentiation igenic transformation [5, 7, 9]. C/EBPβ is expressed as and bone formation: In the absence of C/EBPβ, bone mass three different protein isoforms differing in their N-terminal is decreased [12] due to decreased osteoblast differentiation J Mol Med (2010) 88:227–233 229 and function [11]; however, this appeared to entail also produce osteoprotegerin, a decoy receptor of RANK-L, noncell autonomous effects [3, 13]. C/EBPβ deficiency thereby counteracting and fine tuning the effect of RANK-L also resulted in growth retardation during embryogenesis in osteoclastogenesis. These cytokines activate downstream [11, 14] and at postnatal stages [3], due to diminished osteoclastic transcription factors, including NFATc1, Mitf, chondrocyte differentiation [11, 14]. C/EBPβ activates the and c-Fos that affect proliferation, differentiation, and survival kip cyclin-dependent kinase inhibitor p57 in chondrocytes of osteoclasts [2, 26]. that restricts chondrocyte proliferation and stimulates the Absence of C/EBPβ or expression of only the LIP transition to hypertrophic differentiation [14]. isoform was observed to strongly enhance osteoclast Surprisingly, expression of the (repressor) LIP isoform differentiation. This suggested that the absence of LAP instead of the entire C/EBPβ gene from its endogenous would cause enhanced osteoclastogenesis, and LAP would locus in “knock-in” mouse mutants restored bone formation induce a gene whose product blocks osteoclast differenti- and rescued the growth retardation observed in C/EBPβ- ation. Such an inhibitor was identified as MafB, a deficient animals [3]. Moreover, LIP enhanced osteoblast transcription factor recently found to be involved in differentiation and function [3], possibly by acting as a osteoclastogenesis [4] and a target gene of LAP [3]. coactivator for Runx2 [10]. MafB is also a bZIP transcription factor that, however, Besides cell autonomous effects, C/EBPβ is possibly belongs to a distinct family. MafB is important in several also involved in paracrine action and the coupling between developmental processes [27] and in oncogenesis [28]. In osteoblasts and osteoclasts. C/EBPβ and its related family the hematopoietic system, the function of MafB is restricted member C/EBPδ induce IGF-I expression [15–18] that to the monocytic lineage [29]. Similarly to C/EBPβ, the represents an important anabolic factor for bone formation. expression of MafB starts at the myeloblast stage and Similar to TGFβ [19], IGF-I is released from the bone strongly increases during macrophage differentiation [29]. matrix by osteoclasts and may then stimulate osteoblasts Although not strictly required for macrophage differentia- [20]. In addition, coupling between osteoclasts and osteo- tion, absence of MafB in monocytes results in an altered blasts is thought to involve the cytokines interleukin 6 (IL- phenotype. Absence of MafB reduces F4/80 levels in 6) and tumor necrosis factor alpha (TNFα)[20] that also macrophages [30]. Upon M-CSF treatment, MafB-deficient represent targets of C/EBPβ in osteoclasts [3]. macrophages form multiple extensive cellular extrusions, often branched, known as filopodia [31], a process that also occurs in osteoclasts and that is required for cell migration C/EBPβ as a switch in osteoclast differentiation [32]. MafB directs macrophage versus osteoclast differentia- The first observations suggesting a connection between tion [4], and recently, MafB was reported to restrict M-CSF C/EBPβ and osteoporosis were made over a decade ago in receptor-induced activation of the PU.1 gene [33] that connection with the cytokine IL6. C/EBPβ, in synergy with encodes an early and essential myeloid and osteoclastic NFκB, was found to act downstream of estrogen, involving transcription factor [26]. No bone phenotype has been binding of the estrogen receptor and resulting in suppres- reported of MafB knockout mice so far, possibly due to sion of IL6 gene transcription in osteoblasts [21]. This is of their early postnatal lethality [27]. However, the MafB clinical relevance as decreased estrogen levels are one of protein interacts with and thereby attenuates the activity of the major causes of postmenopausal osteoporosis, which the osteoclastogenic transcription factors NFATc1, Mitf, results in increased IL-6 that activates osteoclasts and thus and c-Fos [4]. The long C/EBPβ isoform LAP induces bone resorption [22, 23]. Indeed, C/EBPβ-deficient mice MafB expression and thus inhibits osteoclastogenesis, show a similar general pathology as mice overexpressing whereas absence of LAP (such as in C/EBPβ-deficient IL6 [24] and with bone loss as a consequence of enhanced animals or in knockin mutants expressing only the activity of osteoclasts [3]. Macrophage defects observed in inhibitory LIP isoform) results in diminished MafB expres- C/EBPβ-deficient mice [25] were the first indication of a sion. Lack of MafB enhances the functionality of NFATc1, possible role of C/EBPβ in the bone-resorbing osteoclast, its downstream target OSCAR, and probably other factors, which shares a monocytic precursor cell with macrophages. including Mitf and c-Fos, to augment expression of In contrast to macrophages, osteoclast precursors fuse into osteoclast genes, including the cell fusion-promoting genes large polykaryons to generate mature osteoclasts that attach to DC-STAMP, ATP6v0d2, and TNFα [34]. The opposing the bone surface and resorb bone matrix. Both differentiation roles of the different C/EBPβ protein isoforms in MafB and osteolytic activity of osteoclasts requires macrophage expression suggest that the C/EBPβ isoform ratio plays a colony-stimulating factor (M-CSF) and membrane-bound fundamental role as an upstream regulator in the initiation receptor activator of NFκB ligand (RANK-L), which are both of osteoclastogenesis and connects MafB expression and osteoclastogenesis to the mTOR pathway (Fig. produced by osteoblasts and by stromal cells. Osteoblasts also 2). 230 J Mol Med (2010) 88:227–233 Fig. 2 C/EBPβ as a master switch in osteoclast differentiation. a The and TNFα (partially derived from [4, 34]). b The LIP isoform of LAP isoform of C/EBPβ induces expression of MafB. MafB binds to C/EBPβ inhibits MafB expression. As a result, MafB becomes and inactivates the osteoclastic transcription factors c-Fos, Mitf, and limiting, and lack of MafB permits access of the osteoclast NFATc1. Inactivation of these key transcription factors prevents transcription factors (often in conjunction with NFATc1 as a major osteoclast differentiation by inhibition of osteoclast target gene osteoclast transcription factor) to activate target genes and osteoclast expression of OSCAR and NFATc1, resulting in inhibition of NFATc1 differentiation target genes, including the cell fusion genes DC-STAMP, ATP6v0d2, Implications for osteolytic diseases as raloxifene, or strontium ranelate [1, 2, 35]. However, bisphosphonates inhibit the bone remodeling cycle, raising Therapies of osteoporosis concentrate on the inhibition of the need for the development of shorter-acting resorption the pathological bone resorption by osteoclasts using inhibitors, which will not affect the bone-remodeling mainly bisphosphonates, but also estrogen-like drugs such process itself too much to ensure continuous repair of Fig. 3 Dual effect of rapamycin on cancer-induced bone loss. a In this hypothetical model, several types of tumor cells with high LIP expression (breast, prostate, lung, multiple myeloma) preferentially generate osteolytic metastasis by activating osteoclasts to release tumor-promoting growth factors (e.g., TGFβ, IGF-I). This results in a continuous cycle of stimu- lation of metastatic cells and bone resorption (derived from [56]). b The vicious circle between tumor and stroma (osteoclasts) may be interrupted by drugs that impinge on translational control, such as rapamycin or its derivatives J Mol Med (2010) 88:227–233 231 microfractures and prevent additional weaknesses of the local bone loss occurs, and rapamycin was found to be skeleton [2]. Therefore, novel therapeutic strategies are beneficial due to its immunosuppressant characteristics [50, required to improve treatment strategies in osteoporosis and 51]. The observation that rapamycin also functions as an other lytic bone diseases. The findings of involvement of antiresorptive agent by modulating the C/EBPβ isoform translational control of C/EBPβ isoforms in directing ratio [3] may suggest a bipartite function [52] as tumor osteoclastogenesis may entail such novel targets for suppressor or immune suppressant and as an osteoclast therapy. Translational control is affected by the antibiotic regulator, as depicted in Fig. 3. rapamycin that specifically inhibits mTOR signaling, Rapamycin’s immunosuppressant action due to modulation resulting in a shift of the C/EBPβ isoform ratio toward of regulatory T cells might raise concerns when used for other the LAP isoform (Fig. 1). Rapamycin treatment thus favors purposes than immunosuppression, e.g., as in cancer patients LAP expression over LIP, which results in enhanced MafB or elderly with osteolytic diseases. Problems in wound healing gene activation and thus inhibition of both osteoclasto- [53] and occurrence of anemia [54] have been reported, genesis and bone resorption. Inhibition of mTOR by although no increase in infectious complications are also rapamycin inhibits osteoclastogenesis not only in mouse reported [55]. [3, 36] but also in human cells [37], suggesting that the It is interesting to note that the downstream C/EBPβ target murine model may provide disease relevant data. Impor- MafB has also been found to be deregulated in the majority of tantly, a derivative of rapamycin has already been shown to multiple myeloma cases [28]. Moreover, C/EBPβ is known inhibit bone loss in an experimental rat model, where to play a central role in inflammation. Both processes have a osteoporosis was induced by ovariectomy [37]. So far, strong impact on osteoclastogenesis and can induce patho- however, no clinical data is available concerning the impact logical bone resorption. The recent identification of the role of rapamycin on bone. Taken together, these data suggest of the C/EBPβ isoform ratio in the control of osteoclast that rapamycin could potentially serve as a therapeutic differentiation and bone resorption may link the pathology of agent in treating osteolytic diseases [38]. these lytic bone diseases to the translational control of a The mTOR signaling pathway is also important in the distinct gene regulator and may thus open new avenues for regulation of autophagy, a process recently proposed to be novel therapeutic approaches. involved in osteoclast function [39, 40]. Rapamycin The usage of rapamycin to direct translational control induces autophagy and therefore might play a role in late might have several potential benefits to treat osteolytic- osteoclastogenesis. This would be in addition to the action associated diseases, as it can attack these diseases at different of rapamycin early in osteoclast differentiation, where it levels. Rapamycin treatment, combined with restraining inhibits differentiation [3]. Autophagy was suggested to osteoclast differentiation, may have combinatorial functions decelerate aging processes [41], as also recently found for in treating osteolytic diseases. However, one has to take into rapamycin that extends the life span of aged mice [42]. This consideration that inhibition of the mTOR pathway could may suggest that dampening mTOR signaling prevents age- have adverse side effects, requiring the development of novel related disease progression, including cancer. rapamycin analogs or novel tissue-specific mTOR inhibitors Along these lines, the LIP isoform has been associated displaying less side effects. with enhanced proliferation of multiple myeloma and breast cancer and in Hodgkin and anaplastic large cell lymphoma. Acknowledgments The authors are grateful to Dr. J Tuckermann A rapamycin derivative was demonstrated to decrease (Leibnitz Institute for Age Research, Jena, Germany) for critically tumor cell proliferation by abrogating LIP expression reading the manuscript. The authors are also thankful to the members [43]. These observations further strengthen the notion that of the Leutz laboratory for helpful discussions. The authors apologize to all those authors whose work was not cited in this minireview due C/EBPβ is an important downstream target of mTOR, to space limitations. This work was supported by the Berliner affecting cell proliferation and differentiation in diverse cell Krebsgesellschaft (LEFF200708). The authors declare that they have types. Moreover, rapamycin has been shown to inhibit no competing financial interests. tumor cell metastasis in an osteosarcoma mouse model Open Access This article is distributed under the terms of the Crea- [44]. 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Journal

Journal of Molecular Medicine (Berlin, Germany) – Pubmed Central

Published: Nov 27, 2009

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