Role of RANK ligand in mediating increased bone resorption in early postmenopausal women

Eghbali-Fatourechi, Guitty; Khosla, Sundeep; Sanyal, Abhik Kumar; Boyle, William J.; Lacey, David L.; Riggs, B. Lawrence

doi:10.1172/jci200317215

Cited by 625 publications

(114 citation statements)

References 49 publications

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“…The pivotal role that Ikeda et al document for c-Jun in osteoclast formation is in keeping with the fact that the anti-bone resorptive effects of estrogen are substantially mediated by c-Jun repression (20). Given that RANKL expression is also enhanced in estrogen-deficient women (21), RANKL → TRAF6 → MAPK kinase 7 (MKK7) → JNK1 → Jun → NFAT signaling is likely pivotal to the pathogenesis of postmenopausal osteoporosis, and inhibition of any of the components will theoretically arrest accelerated bone resorption ( Figure 1). The therapeutic challenge is how to specifically target these intracellular signaling molecules in osteoclasts.…”

Section: Nfat and Ap-1 In 2002 Takayanagi Et Al Identified Nfat2mentioning

confidence: 84%

RANKing c-Jun in osteoclast development

Teitelbaum¹

2004

J. Clin. Invest.

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Section: Nfat and Ap-1 In 2002 Takayanagi Et Al Identified Nfat2mentioning

confidence: 84%

RANKing c-Jun in osteoclast development

Teitelbaum¹

2004

J. Clin. Invest.

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“…Recently a monoclonal antibody against RANKL was shown to produce prolonged inhibition of bone resorption in postmenopausal women (47). It was also shown that RANKL levels were increased on the surface of bone marrow cells from early postmenopausal women who are estrogen deficient (48). However, it has been difficult to demonstrate a role for OPG deficiency in the pathogenesis of osteoporosis, since OPG levels are not consistently altered.…”

Section: Receptor Activator Of Nf-κb Its Ligand and Osteoprotegerinmentioning

confidence: 99%

Pathogenesis of osteoporosis: concepts, conflicts, and prospects

Raisz¹

2005

Journal of Clinical Investigation

1,502

1,042

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Osteoporosis is a disorder in which loss of bone strength leads to fragility fractures. This review examines the fundamental pathogenetic mechanisms underlying this disorder, which include: (a) failure to achieve a skeleton of optimal strength during growth and development; (b) excessive bone resorption resulting in loss of bone mass and disruption of architecture; and (c) failure to replace lost bone due to defects in bone formation. Estrogen deficiency is known to play a critical role in the development of osteoporosis, while calcium and vitamin D deficiencies and secondary hyperparathyroidism also contribute. There are multiple mechanisms underlying the regulation of bone remodeling, and these involve not only the osteoblastic and osteoclastic cell lineages but also other marrow cells, in addition to the interaction of systemic hormones, local cytokines, growth factors, and transcription factors. Polymorphisms of a large number of genes have been associated with differences in bone mass and fragility. It is now possible to diagnose osteoporosis, assess fracture risk, and reduce that risk with antiresorptive or other available therapies. However, new and more effective approaches are likely to emerge from a better understanding of the regulators of bone cell function.Osteoporosis, characterized by the loss of bone mass and strength that leads to fragility fractures, has probably existed throughout human history but only recently became a major clinical problem as human lifespan increased. In the early 19th century, Sir Astley Cooper, a distinguished English surgeon, noted "the lightness and softness that (bones) acquire in the more advanced stages of life" and that "this state of bone . . . favors much the production of fractures" (1). The term osteoporosis was coined by Johann Lobstein at about the same time, but the disorder he described was probably osteogenesis imperfecta (2). In 1940, the American physician and endocrinologist Fuller Albright described postmenopausal osteoporosis and proposed that it was the consequence of impaired bone formation due to estrogen deficiency (3). Subsequently, the concept that there are 2 forms of osteoporosis, one related to estrogen deficiency at the menopause and the other to calcium deficiency and aging of the skeleton, was proposed (4). This has been replaced by the current concept that osteoporosis represents a continuum, in which multiple pathogenetic mechanisms converge to cause loss of bone mass and microarchitectural deterioration of skeletal structure. These factors, coupled with an increased risk of falls, contribute to a high incidence of fragility fractures in osteoporotic patients.There is a rapidly expanding amount of information, based on laboratory studies, that indicates that osteoporosis is likely to be caused by complex interactions among local and systemic regulators of bone cell function. The heterogeneity of osteoporosis may be due not only to differences in the production of systemic and local regulators, but also to changes in receptors, signal tra...

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“…The mechanisms through which estrogen deficiency stimulates bone resorption remain controversial. Direct effects on osteoclasts (2)(3)(4), upregulation of the osteoclast-inductive cytokine RANK ligand (RANKL) (5), or downregulation of its decoy receptor osteoprotegerin in osteoblasts (6) have been reported. In addition, several inflammatory cytokines have been implicated: estrogen has been reported to suppress expression of TNF-α, IL-1, and IL-6 in osteoclast-supportive bone marrow stromal cells, monocytes, and lymphocytes (see refs.…”

Section: Introductionmentioning

confidence: 99%

A crucial role for thiol antioxidants in estrogen-deficiency bone loss

Lean¹,

Davies²,

Fuller³

et al. 2003

J. Clin. Invest.

422

143

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The mechanisms through which estrogen prevents bone loss are uncertain. Elsewhere, estrogen exerts beneficial actions by suppression of reactive oxygen species (ROS). ROS stimulate osteoclasts, the cells that resorb bone. Thus, estrogen might prevent bone loss by enhancing oxidant defenses in bone. We found that glutathione and thioredoxin, the major thiol antioxidants, and glutathione and thioredoxin reductases, the enzymes responsible for maintaining them in a reduced state, fell substantially in rodent bone marrow after ovariectomy and were rapidly normalized by exogenous 17-β estradiol. Moreover, administration of N-acetyl cysteine (NAC) or ascorbate, antioxidants that increase tissue glutathione levels, abolished ovariectomy-induced bone loss, while L-buthionine-(S,R)-sulphoximine (BSO), a specific inhibitor of glutathione synthesis, caused substantial bone loss. The 17-β estradiol increased glutathione and glutathione and thioredoxin reductases in osteoclast-like cells in vitro. Furthermore, in vitro NAC prevented osteoclast formation and NF-κB activation. BSO and hydrogen peroxide did the opposite. Expression of TNF-α, a target for NF-κB and a cytokine strongly implicated in estrogen-deficiency bone loss, was suppressed in osteoclasts by 17-β estradiol and NAC. These observations strongly suggest that estrogen deficiency causes bone loss by lowering thiol antioxidants in osteoclasts. This directly sensitizes osteoclasts to osteoclastogenic signals and entrains ROS-enhanced expression of cytokines that promote osteoclastic bone resorption

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Role of RANK ligand in mediating increased bone resorption in early postmenopausal women

Cited by 625 publications

References 49 publications

RANKing c-Jun in osteoclast development

RANKing c-Jun in osteoclast development

Pathogenesis of osteoporosis: concepts, conflicts, and prospects

A crucial role for thiol antioxidants in estrogen-deficiency bone loss

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