ReviewRegulation of bone metabolism by nuclear receptors
Introduction
In vertebrates, skeletal bones play various physiological roles. Besides its obvious functions in locomotion, protection and support of soft tissues, bones also represent hematopoietic and endocrine organs and regulate calcium homeostasis (Lee et al., 2007). The World Health Organization (WHO) has recognized the importance of achievements in bone research for the improvement of human health and well-being by declaring this decade as a “Bone and Joint Decade” to stimulate further basic and clinical studies of bone physiology and disease.
Osteoporosis, a pathological condition in which bones become increasingly porous and easy to fracture, has become one of the major health and socio-economical problems in many countries. Studies on the etiology and pathology of osteoporosis revealed an intricate complexity in mechanisms of regulation of bone physiology. This complexity represents an enormous challenge in search of therapeutic targets and development of efficient treatment strategies.
Insufficient calcium uptake or its excessive excretion triggers bone calcium mobilization causing bone growth retardation in infants and osteopenia leading to osteoporosis in adults. Vitamin D has long been known as a potent stimulant of calcium absorption and food supplement for maintenance of bone strength and prevention of osteoporosis (Weaver, 2007). Combination with vitamin D markedly increases the efficacy of anti-catabolic agents, bisphosphonates, widely used for the treatment of osteoporosis (Rosen et al., 2005, Russell, 2006, Russell et al., 2007).
Estrogen deficiency is another well-established cause of osteoporosis. Hormone replacement therapy (HRT) has been very successful in prevention of bone loss in post-menopausal women. Unfortunately, intake of estrogens during HRT increased the risk of estrogen-sensitive malignancies, such as breast cancer (Harman, 2006, Nelson et al., 2002). Discovery of selective estrogen receptor modulators (SERMs) that do not produce at therapeutic doses undesirable side effects opened new possibilities of HRT in treatment of post-menopausal osteoporosis (Draper, 2003, Miller et al., 2008, Rosen, 2005). Post-menopausal osteoporosis in men is less studied than in women. Nevertheless, several clinical studies indicate that androgen deficiency is detrimental for the bone mineral density (BMD) in men (Ebeling, 2008).
Thus, vitamin D, estrogens and androgens play pivotal roles in bone physiology. Biological action of these hormones is mediated by their cognate nuclear receptors (NR), vitamin D receptor (VDR), estrogen receptors α and β (ERα and ERβ) and androgen receptor (AR), respectively. Therefore, success in development of beneficial therapeutic strategies for treatment of bone diseases depends on our understanding of NR biological functions. This review is aimed to briefly summarize recent progress in studies on molecular mechanisms of NR action in bone tissue.
Section snippets
Bone tissue cells
Bone tissue is composed of cells and mineralized extracellular matrix and constantly undergoes remodeling through coordinated processes of bone resorption and formation (Karsenty, 2006, Raisz, 2005). There are three distinct bone cell types. The osteoblasts are derived from mesenchymal stem cells and responsible for bone formation. The osteoclasts are differentiated from hematopoietic stem cells into macrophage lineage multinucleated giant cells responsible for bone resorption. Though bones
Genetic approaches in elucidation of cell-specific action of nuclear hormone receptors
Nuclear hormone receptors represent a major group of regulatory factors that control critical processes of bone growth and metabolism (Teitelbaum and Ross, 2003, Zaidi, 2007). They constitute a superfamily of ligand-dependent transcriptional factors that regulate expression of target genes through binding at their promoters to specific receptor recognition element DNA sequences (Mangelsdorf et al., 1995, McKenna and O’Malley, 2002). Promoter-bound NR recruits various co-factors that include
Vitamin D receptor function in bone
The biologically active form of vitamin D is dihydroxy vitamin D3 (1,25(OH)2D3). Insufficient intake of vitamin D is known as rickets (Holick, 2006), and leads to bone growth retardation and bone mineral metabolism disorder. Complete loss of function VDR mutations in humans leads to development of type 2 rickets with characteristic alopecia and bone growth abnormalities (Haussler et al., 1998).
VDR gene knockout (VDRKO) in mice produced phenotype closely resembling type 2 rickets in humans. The
Glucocorticoid receptor (GR) function in bone
Glucocorticoids (GC) facilitate bone resorption, decrease bone formation and consequently lead to a decrease in bone mass (Canalis, 1996, Ishida and Heersche, 1998). High levels of glucocorticoids in vivo, as a result of prolonged steroid therapy or Cushing's syndrome, are associated with decrease in BMD and osteopenia, leading to the development of osteoporosis (Henderson and Sambrook, 1996, Lukert, 1990, Lukert and Raisz, 1990, Osella et al., 1997, Pearce et al., 1998). Severity of the bone
Androgen receptor (AR) function in bone tissue
It is commonly known that male bones have higher mineral density and lower risk of fracture or osteoporosis than female (Vanderschueren et al., 2004). Decrease in testosterone is associated with many symptoms and signs of aging such as decrease in muscle mass and strength, cognitive decline, decrease in bone mass, and increase in (abdominal) fat mass (Emmelot-Vonk et al., 2008).
The anabolic effects of androgenic hormones have been thought to increase mineral density and strength of male bones.
Estrogen deficiency in etiology of osteoporosis
A menopause-triggered decrease in bone mineral density and high turnover bone metabolism leads to development of the post-menopausal osteoporosis (Syed and Khosla, 2005). Ovariectomy-induced estrogen deficiency lead to similar bone defects in experimental animals. Treatment with estrogens restored normal bone mass and turnover in post-menopausal women and ovariectomized animals (Hukkanen et al., 2003, Wu et al., 2001). This suggests that estrogens exert bone-protective effects via action of
Estrogen receptors function in bone tissue
Between two existing isoforms, ERα is the main receptor mediating estrogen action in majority of target organs and cells. Unexpectedly, mice with ablated ERα gene, ERαKO mice, exhibited increased BV/TV (bone volume/tissue volume) regardless of sex (Sims et al., 2002). Bone morphometric analysis in ERαKO mice revealed low turnover bone metabolism with decreased numbers of osteoclasts and osteoblasts, and reduced rates of bone resorption and bone formation. Trabecular BMD was increased in the
Generation of osteoclast-specific Cre recombinase expression mice
Expression of sex steroid hormone receptors has been confirmed in the osteoblasts, however, that in the osteoclasts were undetectable. Therefore, it remained unclear whether osteoclasts were not steroid target cells or expression of sex hormone receptors in osteoclasts was below the sensitivity of detection methods. To address this question we have employed a cell-targeted gene deletion method using Cre/loxP system (Li et al., 2000) to establish potential biological function of sex steroid
Estrogens prevent bone loss though induction of apoptosis in osteoclasts
The osteoclast-specific ERαKO mice (ERαΔOc/ΔOc) has been generated using ERαflox mice (Dupont et al., 2000) and Ctsk-Cre mice described above.
From the results of bone histomorphometrical and radiological analysis, only female ERαΔOc/ΔOc mice exhibited trabecular bone loss in distal femora as well as vertebral bodies. Detailed bone histomorphometry showed high turnover bone metabolism with increase in osteoclast numbers in female ERαΔOc/ΔOc. Significantly, ovariectomy lead to increase in
Summary
Despite well-established significance of nuclear receptors in bone physiology, molecular mechanisms of their action in bone tissues remain elusive. Total ablation of receptor genes in general, or conventional gene knockout approach only further underscored the importance of nuclear receptors in regulation of bone functions. It has failed, however, to identify direct targets and cell-specificity in receptor actions due to systemic and pleiotropic effects of the respective hormones. Development
Acknowledgements
This work was supported in part by a Priority area grant from the Ministry of Education, Culture, Sports, Science and Technology and the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN) (to S.K.) and a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Project Grants 19791018 to Y.I.).
References (94)
- et al.
Osteocytes, mechanosensing and Wnt signaling
Bone
(2008) Estrogen replacement in menopausal women: recent and current prospective studies, the WHI and the KEEPS
Gend. Med.
(2006)- et al.
Effect of nitric oxide donor nitroglycerin on bone mineral density in a rat model of estrogen deficiency-induced osteopenia
Bone
(2003) Convergence between bone and energy homeostases: leptin regulation of bone mass
Cell Metab.
(2006)- et al.
Endocrine regulation of energy metabolism by the skeleton
Cell
(2007) - et al.
The nuclear receptor superfamily: the second decade
Cell
(1995) - et al.
Combinatorial control of gene expression by nuclear receptors and coregulators
Cell
(2002) - et al.
Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts
Cell
(2007) - et al.
Cortisol inhibits the differentiation and apoptosis of osteoblasts in culture
Bone
(2001) - et al.
Effects of cortisol and bone morphogenetic protein-2 on stromal cell differentiation: correlation with CCAAT-enhancer binding protein expression
Bone
(2002)