Evidence for osteocyte regulation of bone homeostasis through RANKL expression

Nakashima, Tomoki; Hayashi, Muneaki; Fukunaga, Takanobu; Kurata, K.; Oh‐hora, Masatsugu; Feng, Jian Q.; Bonewald, Lynda F.; Kodama, Tatsuhiko; Wutz, Anton; Wagner, Erwin F.; Penninger, Josef; Takayanagi, Hiroshi

doi:10.1038/nm.2452

Cited by 1,518 publications

(1,298 citation statements)

References 19 publications

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“…Although we did not identify the specific cell source impacted by renal dysfunction, recent evidence has found that the osteocyte is the primary source of RANKL and its negative regulator OPG, and hence plays a major role in supporting osteoclastogenesis. (31,68) Osteocyte-specific deletion of RANKL in mice causes an osteopetrotic phenotype resulting from a significant decrease in osteoclast number and surface. (31) These data extend previous reports demonstrating that osteocyte-specific deletion of b-catenin is associated with an increase in the RANKL/OPG ratio, thereby supporting a role of this signaling pathway in balancing the expression of these opposing factors.…”

Section: Discussionmentioning

confidence: 99%

“…(31,68) Osteocyte-specific deletion of RANKL in mice causes an osteopetrotic phenotype resulting from a significant decrease in osteoclast number and surface. (31) These data extend previous reports demonstrating that osteocyte-specific deletion of b-catenin is associated with an increase in the RANKL/OPG ratio, thereby supporting a role of this signaling pathway in balancing the expression of these opposing factors. (34) In vitro experiments using primary and established osteocyte cells have demonstrated that the Wnt inhibitor, sclerostin, stimulates RANKL expression, leading to an increase in the RANKL/OPG mRNA ratio favoring the formation of TRAP þ multinucleated cells.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, new evidence suggests that the osteocyte is a prominent source of bone remodeling factors, including receptor activator of NF-kB ligand (RANKL), osteoprotegerin (OPG), and sclerostin, because these influence osteoclast and osteoblast activity. (30)(31)(32)(33)(34) Furthermore, modulation of the WNT/b-catenin pathway has recently been shown to regulate osteoclast activity by altering the osteocyte RANKL/OPG ratio. (34) Our data demonstrate that repression of the Wnt/b-catenin pathway within osteocytes occurs in parallel with an increase in the RANKL/OPG ratio and osteoclast activity.…”

Section: Introductionmentioning

confidence: 99%

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Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

239

224

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Chronic kidney disease–mineral bone disorder (CKD‐MBD) is defined by abnormalities in mineral and hormone metabolism, bone histomorphometric changes, and/or the presence of soft‐tissue calcification. Emerging evidence suggests that features of CKD‐MBD may occur early in disease progression and are associated with changes in osteocyte function. To identify early changes in bone, we utilized the jck mouse, a genetic model of polycystic kidney disease that exhibits progressive renal disease. At 6 weeks of age, jck mice have normal renal function and no evidence of bone disease but exhibit continual decline in renal function and death by 20 weeks of age, when approximately 40% to 60% of them have vascular calcification. Temporal changes in serum parameters were identified in jck relative to wild‐type mice from 6 through 18 weeks of age and were subsequently shown to largely mirror serum changes commonly associated with clinical CKD‐MBD. Bone histomorphometry revealed progressive changes associated with increased osteoclast activity and elevated bone formation relative to wild‐type mice. To capture the early molecular and cellular events in the progression of CKD‐MBD we examined cell‐specific pathways associated with bone remodeling at the protein and/or gene expression level. Importantly, a steady increase in the number of cells expressing phosphor‐Ser33/37‐β‐catenin was observed both in mouse and human bones. Overall repression of Wnt/β‐catenin signaling within osteocytes occurred in conjunction with increased expression of Wnt antagonists (SOST and sFRP4) and genes associated with osteoclast activity, including receptor activator of NF‐κB ligand (RANKL). The resulting increase in the RANKL/osteoprotegerin (OPG) ratio correlated with increased osteoclast activity. In late‐stage disease, an apparent repression of genes associated with osteoblast function was observed. These data confirm that jck mice develop progressive biochemical changes in CKD‐MBD and suggest that repression of the Wnt/β‐catenin pathway is involved in the pathogenesis of renal osteodystrophy. © 2012 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Sabbagh

Graciolli

O’Brien

et al. 2012

Journal of Bone and Mineral Research

239

224

View full text Add to dashboard Cite

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“…As a major function, osteocytes are thought to respond to mechanical strain and accordingly exert biochemical signals that regulate the activities of osteoblasts and osteoclasts. [4][5][6][7][8][9] Osteocytes also function as endocrine cells by producing fibroblast growth factor 23 (FGF23), which regulates calcium and phosphate homeostasis targeting tissues other than bone, such as the kidneys. 3,10,11 FGF23 was originally identified in the ventrolateral thalamic nucleus of the brain.…”

Section: Introductionmentioning

confidence: 99%

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

2014

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Fibroblast growth factor 23 (FGF23) and dentin matrix protein (DMP1) are hallmarks of osteocytes in bone. However, the mechanisms underlying the actions of DMP1 as a local factor regulating FGF23 and bone mineralization are not well understood. We first observed spatially distinct distributions of FGF23-and DMP1-positive osteocytic lacunae in rat femurs using immunohistochemistry. Three-dimensional immunofluorescence morphometry further demonstrated that the distribution and relative expression levels of these two proteins exhibited reciprocally reversed patterns especially in midshaft cortical bone. These in vivo findings suggest a direct role of DMP1 in FGF23 expression in osteocytes. We next observed that the inoculation of recombinant DMP1 in UMR-106 osteoblast/osteocyte-like cells and long-cultured MC3T3-E1 osteoblastic cells showed significant downregulation of FGF23 production. This effect was rescued by incubation with an focal adhesion kinase (FAK) inhibitor or MEK (mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)) inhibitor but not inhibitors of phosphoinositide 3-kinase or Rho kinase. Consistently, the levels of phosphorylated FAK, ERK and p38 were significantly elevated, indicating that exogenous DMP1 is capable of activating FAK-mediated MAPK signaling. These findings suggest that DMP1 is a local, direct and negative regulator of FGF23 production in osteocytes involved in the FAK-mediated MAPK pathway, proposing a relevant pathway that coordinates the extracellular environment of osteocytic lacunae and bone metabolism.

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“…(16) Moreover, osteocytes express a number of potentially important genes such as receptor activator of NF-kB ligand (RANKL), which are involved in bone remodeling and which might be androgen regulated. (17) Because the impact of inactivation of androgen action through the AR in osteocytes in vivo has not been determined, we generated and characterized a mouse model in which the AR is deleted specifically in terminally differentiated osteocytes using the dentin matrix protein 1 (DMP1) Cre mouse line (18) and the Cre/LoxP system (ocy-ARKO). This ocy-ARKO mouse line targets AR action in a more differentiated population of osteocytes than in a previously described osteoblast ARKO model.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

Sinnesael

Claessens

Laurent

et al. 2012

Journal of Bone and Mineral Research

102

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Androgens play a key role in the maintenance of male skeletal integrity. The regulation of this integrity by androgen receptor (AR) signaling has been mainly attributed to osteoblasts. Although osteocytes have emerged as key regulators of bone remodeling, the influence of sex steroids on these cells has been poorly studied. We aimed to investigate the role of AR signaling, specifically in osteocytes using the Cre/LoxP system in male mice (driven by dentin matrix protein 1 [ocy-ARKOs]). Osteocyte fractions of control (AR(ex2)/Y) and ocy-ARKO (ARflox(ex2)/Y; DMP1-cre) mice isolated through sequential collagenase digestion showed increasing AR expression toward the mature osteocyte fraction of control males compared with the more immature fractions, whereas this was reduced by >80% in ocy-ARKO osteocytes. The skeletal phenotype of mutant mice was further assessed by histomorphometry and quantitative micro-computed tomography at 12 and 32 weeks of age. Ocy-ARKOs had significantly lower trabecular bone volume and number in femora and tibias at 32 weeks as well as decreased trabecular number in the L 5 vertebra at 12 weeks. Biomechanical testing showed that ocy-ARKO femora were also stiffer and required a lower ultimate force to induce failure at 32 weeks. However, femoral cortical structure was not significantly different at any time point. The absence of AR in osteocyte also did not appear to affect trabecular bone formation nor its response to mechanical loading. In conclusion, selective inactivation of the AR in osteocytes of male mice accelerates age-related deterioration of skeletal integrity. These findings provide evidence for a direct role of androgens in the maintenance of trabecular bone through actions of the AR in osteocytes. ß

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Evidence for osteocyte regulation of bone homeostasis through RANKL expression

Cited by 1,518 publications

References 19 publications

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

Functional heterogeneity of osteocytes in FGF23 production: the possible involvement of DMP1 as a direct negative regulator

Androgen receptor (AR) in osteocytes is important for the maintenance of male skeletal integrity: Evidence from targeted AR disruption in mouse osteocytes

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