Osteoprotegerin Ligand Modulates Murine Osteoclast Survival in Vitro and in Vivo

Lacey, David L.; Tan, Hong; Lu, John; Sl, Kaufman; Van, Gwyneth; Qiu, Wanrang; Rattan, Alana; Scully, Sheila; Fletcher, Frederick A.; Juan, Todd; Kelley, Michael J.; Burgess, Teresa L.; Boyle, William J.; Polverino, Anthony

doi:10.1016/s0002-9440(10)64556-7

Cited by 369 publications

(250 citation statements)

References 33 publications

Supporting

Mentioning

237

Contrasting

Unclassified

Order By: Relevance

“…1). Mice lacking the TNFR superfamily member RANK, or its cognate ligand (RANKL), are also osteopetrotic because of a cell autonomous defect in osteoclast differentiation from hematopoietic precursors (4, 10, 11), yet it is understood that RANKL affects multiple, diverse steps in the osteoclastogenic genetic program including osteoclast differentiation (6,8), survival (9), and stimulation of resorptive function (7,34). Because each of the steps may contribute to enhanced bone turnover during pathologic conditions such as osteoporosis, bone loss resulting from inflammatory diseases or malignancies (1), it is important to define the signal transduction cascades emanating from RANK that are responsible for these pleiotropic actions.…”

Section: Discussionmentioning

confidence: 99%

“…RANKL affects bone resorption and bone density by influencing the osteoclast population at multiple stages. Not only does RANKL drive the differentiation of osteoclasts from multipotential progenitors, thereby expanding the pool of osteoclasts available for bone resorption (6), RANKL also activates resorption and enhances survival of existing mature osteoclasts in vitro (7,8) and in vivo (9). An essential role for the RANKL receptor, RANK, in osteoclast differentiation in vivo is demonstrated by the lack of osteoclasts and resulting osteopetrosis in RANKϪ/Ϫ animals (10,11).…”

mentioning

confidence: 99%

See 1 more Smart Citation

A RANK/TRAF6-dependent Signal Transduction Pathway Is Essential for Osteoclast Cytoskeletal Organization and Resorptive Function

Armstrong¹,

Tometsko²,

Glaccum

et al. 2002

Journal of Biological Chemistry

217

143

View full text Add to dashboard Cite

Signaling through receptor activator of nuclear factor-B (RANK) is essential for the differentiation and activation of osteoclasts, the cell principally responsible for bone resorption. Animals genetically deficient in RANK or the cognate RANK ligand are profoundly osteopetrotic because of the lack of bone resorption and remodeling. RANK provokes biochemical signaling via the recruitment of intracellular tumor necrosis factor receptor-associated factors (TRAFs) after ligand binding and receptor oligomerization. To understand the RANK-mediated signal transduction mechanism in osteoclastogenesis, we have designed a system to recapitulate osteoclast differentiation and activation in vitro by transfer of the RANK cDNA into hematopoietic precursors genetically deficient in RANK. Gene transfer of RANK constructs that are selectively incapable of binding different TRAF proteins revealed that TRAF pathways downstream of RANK that affect osteoclast differentiation are functionally redundant. In contrast, the interaction of RANK with TRAF6 is absolutely required for the proper formation of cytoskeletal structures and functional resorptive activity of osteoclasts. Moreover, signaling via the interleukin-1 receptor, which also utilizes TRAF6, rescues the osteoclast activation defects observed in the absence of RANK/TRAF6 interactions. These studies are the first to define the functional domains of the RANK cytoplasmic tail that control specific differentiation and activation pathways in osteoclasts.The structural and metabolic integrity of bone is maintained through the dynamic process of bone remodeling that results from the coordinate action of bone resorption by osteoclasts and the formation of new bone by osteoblasts. Osteoclasts are large, multinuclear cells that develop from a hematopoietic progenitor and are highly specialized for the resorptive process (1). Regulation of bone remodeling occurs through multiple mechanisms that ultimately converge on the interaction of osteoclasts or their precursors with osteoblasts and bone marrow stromal cells. Two key factors supplied by the stromal environment are CSF-1 1 and the TNF family member, RANKL (also called TRANCE, ODF, OPGL) (2), as confirmed by the osteopetrotic phenotypes of the op/op mice that are mutated in the CSF-1 gene (3) and the RANKL knockout mice (4).It is now widely accepted that most osteotropic agents including IL-1, IL-6, IL-11, IL-17, TNF-␣, prostaglandin E 2 , parathyroid hormone, and 1,25-dihydroxyvitamin D 3 (5) affect bone resorption primarily by enhancing stromal cell production of RANKL. RANKL affects bone resorption and bone density by influencing the osteoclast population at multiple stages. Not only does RANKL drive the differentiation of osteoclasts from multipotential progenitors, thereby expanding the pool of osteoclasts available for bone resorption (6), RANKL also activates resorption and enhances survival of existing mature osteoclasts in vitro (7,8) and in vivo (9). An essential role for the RANKL receptor, RANK, in osteoclast differenti...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A RANK/TRAF6-dependent Signal Transduction Pathway Is Essential for Osteoclast Cytoskeletal Organization and Resorptive Function

Armstrong¹,

Tometsko²,

Glaccum

et al. 2002

Journal of Biological Chemistry

217

143

View full text Add to dashboard Cite

show abstract

“…The receptor for this ligand, RANK, is a high-affinity receptor of osteoclast precursors, as well as T and B cells, fibroblasts and dendritic cells (Anderson et al 1997). When unopposed, RANKL binds RANK and induces osteoclast formation in the presence of Macrophage (M)-colony stimulating factor (M-CSF) (Lacey et al 2000). OPG, a member of the tumour necrosis factor (TNF) receptor superfamily, is a secreted RANKL decoy receptor of osteoblastic-lineage cells (Simonet et al 1997, Yasuda et al 1998.…”

Section: Normal Bone Remodelling and Calcium Homeostasis Bone Remodelmentioning

confidence: 99%

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

Clines

Guise²

2005

Endocr Relat Cancer

230

211

View full text Add to dashboard Cite

Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the 'seed and soil' hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-b that further stimulates local cancer cells. This 'vicious cycle' of bone metastases represents reciprocal bone/ cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the 'vicious cycle' is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.

show abstract

“…16 Soluble RANKL (sRANKL) and TNFa have also been shown to support Ocl survival in addition to their effect on differentiation. 17,18 However, a common mechanism, if any, by which these prosurvival cytokines exert antiapoptotic effects in Ocl remains unknown.…”

Section: Introductionmentioning

confidence: 99%

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

et al. 2003

View full text Add to dashboard Cite

Multinucleated bone-resorbing osteoclasts (Ocl) are cells of hematopoietic origin that play a major role in osteoporosis pathophysiology. Ocl survival and activity require M-CSF and RANK ligand (RANKL). M-CSF signals to Akt, while RANKL, like TNFa, activates NF-jB. We show here that although these are separate pathways in the Ocl, signaling of all three cytokines converges on mammalian target of rapamycin (mTOR) as part of their antiapoptotic action. Accordingly, rapamycin blocks M-CSF-and RANKL-dependent Ocl survival inducing apoptosis, and suppresses in vitro bone resorption proportional to the reduction in Ocl number. The cytokine signaling intermediates for mTOR/ribosomal protein S6 kinase (S6K) activation include phosphatidylinositol-3 kinase, Akt, Erks and geranylgeranylated proteins. Inhibitors of these intermediates suppress cytokine activation of S6K and induce Ocl apoptosis. mTOR regulates protein translation acting via S6K, 4E-BP1 and S6. We find that inhibition of translation by other mechanisms also induces Ocl apoptosis, demonstrating that Ocl survival is highly sensitive to continuous de novo protein synthesis. This study thus identifies mTOR/S6K as an essential signaling pathway engaged in the stimulation of cell survival in osteoclasts.

show abstract

Osteoprotegerin Ligand Modulates Murine Osteoclast Survival in Vitro and in Vivo

Cited by 369 publications

References 33 publications

A RANK/TRAF6-dependent Signal Transduction Pathway Is Essential for Osteoclast Cytoskeletal Organization and Resorptive Function

A RANK/TRAF6-dependent Signal Transduction Pathway Is Essential for Osteoclast Cytoskeletal Organization and Resorptive Function

Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

M-CSF, TNFα and RANK ligand promote osteoclast survival by signaling through mTOR/S6 kinase

Contact Info

Product

Resources

About