Review
Regulation of bone metabolism by nuclear receptors

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Abstract

Bone tissue protects and supports soft organs and maintains calcium homeostasis. Steroid sex hormones and fat-soluble vitamins play a pivotal role in regulation of bone homeostasis, turnover and remodeling. These molecules act as ligands of nuclear receptors, through which they control gene expression in bone cells, namely bone-forming osteoblasts, bone-resorptive osteoclasts and osteocytes. Significant advances in our understanding of nuclear receptor physiology have been achieved due to development of novel genetic manipulation approaches and generation of experimental animal models in which nuclear receptor genes were mutated in specific cell types. In this review, we summarized some aspects of recent progress in studies on molecular mechanisms of cell-specific action of nuclear hormone receptors in bone tissue.

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 (ERαΔOcOc) 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 ERαΔOcOc 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 ERαΔOcOc. 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)

  • K. Sakai et al.

    A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission

    Biochem. Biophys. Res. Commun.

    (1997)
  • M.J. Seibel et al.

    Sex steroids, not FSH, influence bone mass

    Cell

    (2006)
  • N.A. Sims et al.

    Deletion of estrogen receptors reveals a regulatory role for estrogen receptors-beta in bone remodeling in females but not in males

    Bone

    (2002)
  • S. Srivastava et al.

    Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation

    J. Biol. Chem.

    (2001)
  • L. Sun et al.

    FSH directly regulates bone mass

    Cell

    (2006)
  • F. Syed et al.

    Mechanisms of sex steroid effects on bone

    Biochem. Biophys. Res. Commun.

    (2005)
  • T. Takahashi et al.

    Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand

    Cell

    (1994)
  • S. Tatsumi et al.

    Targeted ablation of osteocytes induces osteoporosis with defective mechanotransduction

    Cell Metab.

    (2007)
  • R.S. Weinstein et al.

    Apoptosis and osteoporosis

    Am. J. Med.

    (2000)
  • S.H. Windahl et al.

    Elucidation of estrogen receptor function in bone with the use of mouse models

    Trends Endocrinol. Metab.

    (2002)
  • T. Akune et al.

    PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors

    J. Clin. Invest.

    (2004)
  • J.E. Aubin

    Osteoprogenitor cell frequency in rat bone marrow stromal populations: role for heterotypic cell–cell interactions in osteoblast differentiation

    J. Cell Biochem.

    (1999)
  • E. Canalis

    Clinical review 83: mechanisms of glucocorticoid action in bone: implications to glucocorticoid-induced osteoporosis

    J. Clin. Endocrinol. Metab.

    (1996)
  • W.S. Chiu et al.

    Transgenic mice that express Cre recombinase in osteoclasts

    Genesis

    (2004)
  • B.E. Clausen et al.

    Conditional gene targeting in macrophages and granulocytes using LysMcre mice

    Transgenic Res.

    (1999)
  • T.J. Cole et al.

    Targeted disruption of the glucocorticoid receptor gene blocks adrenergic chromaffin cell development and severely retards lung maturation

    Genes Dev.

    (1995)
  • B. Devleta et al.

    Hypergonadotropic amenorrhea and bone density: new approach to an old problem

    J. Bone Miner. Metab.

    (2004)
  • M.W. Draper

    The role of selective estrogen receptor modulators (SERMs) in postmenopausal health

    Ann. N.Y. Acad. Sci.

    (2003)
  • S. Dupont et al.

    Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes

    Development

    (2000)
  • P.R. Ebeling

    Clinical practice. Osteoporosis in men

    N. Engl. J. Med.

    (2008)
  • M.H. Emmelot-Vonk et al.

    Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial

    JAMA

    (2008)
  • J.Q. Feng et al.

    Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism

    Nat. Genet.

    (2006)
  • M. Ferron et al.

    Targeted expression of Cre recombinase in macrophages and osteoclasts in transgenic mice

    Genesis

    (2005)
  • L.A. Fitzpatrick

    Estrogen therapy for postmenopausal osteoporosis

    Arq. Bras. Endocrinol. Metabol.

    (2006)
  • D. Forrest et al.

    Genetic analysis of thyroid hormone receptors in development and disease

    Recent Prog. Horm. Res.

    (1996)
  • A. Fraichard et al.

    The T3R alpha gene encoding a thyroid hormone receptor is essential for post-natal development and thyroid hormone production

    EMBO J.

    (1997)
  • S. Gothe et al.

    Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary–thyroid axis, growth, and bone maturation

    Genes Dev.

    (1999)
  • M. Gowen et al.

    Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization

    J. Bone Miner. Res.

    (1999)
  • T.S. Griffith et al.

    Fas ligand-induced apoptosis as a mechanism of immune privilege

    Science

    (1995)
  • M.R. Haussler et al.

    The nuclear vitamin D receptor: biological and molecular regulatory properties revealed

    J. Bone Miner. Res.

    (1998)
  • N.K. Henderson et al.

    Relationship between osteoporosis and arthritis and effect of corticosteroids and other drugs on bone

    Curr. Opin. Rheumatol.

    (1996)
  • M.F. Holick

    Resurrection of vitamin D deficiency and rickets

    J. Clin. Invest.

    (2006)
  • Y. Ishida et al.

    Glucocorticoid-induced osteoporosis: both in vivo and in vitro concentrations of glucocorticoids higher than physiological levels attenuate osteoblast differentiation

    J. Bone Miner. Res.

    (1998)
  • H. Kawano et al.

    Suppressive function of androgen receptor in bone resorption

    Proc. Natl. Acad. Sci. U.S.A.

    (2003)
  • H.J. Kim et al.

    Glucocorticoids suppress bone formation via the osteoclast

    J. Clin. Invest.

    (2006)
  • S.A. Krum et al.

    Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival

    EMBO J.

    (2008)
  • T.R. Kumar

    What have we learned about gonadotropin function from gonadotropin subunit and receptor knockout mice?

    Reproduction

    (2005)
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