Deletion of vitamin D receptor leads to premature emphysema/COPD
by increased matrix metalloproteinases and lymphoid aggregates formation
Isaac K. Sundar
a
, Jae-Woong Hwang
a
, Shaoping Wu
b
, Jun Sun
b,c,d
, Irfan Rahman
a,
⇑
a
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Box 850, 601 Elmwood Avenue, Rochester, NY 14642, USA
b
Department of Medicine, Gastroenterology and Hepatology Division, University of Rochester Medical Center, Rochester, NY, USA
c
The Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY, USA
d
The James Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY, USA
article info
Article history:
Received 29 January 2011
Available online 12 February 2011
Keywords:
Vitamin D receptor
Vitamin D
Inflammation
Metalloproteinases
Lung
COPD
abstract
Deficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for
nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The
level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led
us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are char-
acteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR
knock-out (VDR
–/–
) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear fac-
tor-kappaB (NF-
j
B) associated with increased proinflammatory mediators, and up-regulation of matrix
metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphy-
sema and decline in lung function associated with lymphoid aggregates formation compared to WT mice.
These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/
COPD because of chronic inflammation, immune dysregulation, and lung destruction.
Ó 2011 Elsevier Inc. All rights reserved.
1. Introduction
Vitamin D deficiency has become an important global public-
health problem with an estimate of more than 1 billion people
worldwide having low/insufficient serum levels of vitamin D [1–
4]. Vitamin D deficiency is linked to decline in lung function, re-
duced immunity, and increased inflammation [4–9]. Hence, studies
to understand the role of vitamin D in pathogenesis of lung dis-
eases with respect to vitamin D, vitamin D receptor (VDR) and vita-
min D-binding protein are considerable interests [6].
Vitamin D belongs to a steroid hormone superfamily of nuclear
receptors that has pleotropic protective effects on several diseases
and disorders including asthma and chronic obstructive pulmon-
ary disease (COPD) [4,7,8]. 1,25(OH)
2
D
3
(1,25-dihydroxyvitamin
D
3
) an active metabolite of vitamin D (which binds to nuclear
receptor VDR and interacts with other steroid hormone receptors),
is a potent regulator of the immune response in Th1 cell-directed
diseases [10,11]. Ligand binding activates VDR, which forms a het-
erodimer with its partner, the retinoid X receptor (RXR), and this
complex VDR/RXR further binds to specific genomic sequences in
the promoter region of target genes (vitamin D response elements)
and thus recruit transcription factors and co-regulatory molecules
to activate or suppress gene transcription [12,13].
Vitamin D and VDR are important regulators of inflammation in
the lungs. Recent epidemiological studies showed a significant cor-
relation between low serum concentrations of 25-hydroxy vitamin
D and chronic lung diseases, such as asthma [14] and COPD [4], and
accelerated decline in lung function [2,7]. However, the molecular
mechanisms underlying these phenomena are not known. It may
be possible that vitamin D or VDR deficiency would invoke lung
inflammation and alteration in lung function by proteinase/anti-
proteinase imbalance. Lung levels of VDR protein is decreased in pa-
tients with COPD which led us to hypothesize that VDR deficiency
in mouse (VDR
–/–
mice) can lead to abnormal lung phenotype,
due to differential modulation of signaling mediators, and immune
dysfunction further leading to spontaneous airspace enlargement
and altered lung function. We tested the hypothesis by studying
the lung inflammatory cellular influx, posttranslational modifica-
tions (phosphorylation and acetylation) of NF-
j
B RelA/p65, levels
of proinflammatory mediators, levels/activities of extracellular ma-
trix proteins, mean airspace enlargement, lymphoid aggregates for-
mation and pulmonary function in lungs of VDR
–/–
mice.
2. Materials and methods
2.1. Reagents
Unless otherwise stated, all biochemical reagents used in this
study were purchased from Sigma Chemicals (St. Louis, MO). Anti-
0006-291X/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbrc.2011.02.011
⇑
Corresponding author. Fax: +1 585 276 0239.
E-mail address: irfan_rahman@urmc.rochester.edu (I. Rahman).
Biochemical and Biophysical Research Communications 406 (2011) 127–133
Contents lists available at ScienceDirect
Biochemical and Biophysical Research Communications
journal homepage: www.elsevier.com/locate/ybbrc