Sclerostin Stimulates Osteocyte Support of Osteoclast Activity by a RANKL-Dependent Pathway

Wijenayaka, Asiri R.; Kogawa, Masakazu; Lim, Hui Peng; Bonewald, Lynda F.; Findlay, David M.; Atkins, Gerald J.

doi:10.1371/journal.pone.0025900

Cited by 456 publications

(341 citation statements)

References 62 publications

(96 reference statements)

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“…Therefore, taken together with previous studies (13,14), our findings demonstrate that β-catenin activation increases OPG in all cells of the osteoblastic lineage, whereas it only increases RANKL in osteocytes that also express Sost. Our results are consistent with earlier studies demonstrating that elevated expression of Sost/sclerostin up-regulates RANKL (19,37) and increases osteoclasts (37). Expression of M-CSF is also elevated in daßcat Ot mice, consistent with our recent findings demonstrating that M-CSF is a downstream target of RANKL in osteocytes (38).…”

Section: Discussionsupporting

confidence: 93%

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Tu¹,

Delgado‐Calle

Condon³

et al. 2015

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

244

237

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Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcat Ot mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat Ot mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat Ot mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat Ot mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.osteocytes | canonical Wnt | beta-catenin | bone anabolism | notch signaling

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Section: Discussionsupporting

confidence: 93%

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Tu¹,

Delgado‐Calle

Condon³

et al. 2015

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

244

237

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“…(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. (68) These studies are also in agreement with our data demonstrating that the increased sclerostin expression observed early in CKD-MBD leads to a concomitant increase in RANKL expression that may drive osteoclastogenesis, which was associated with increased bone formation rates in the jck mouse.…”

Section: Discussionsupporting

confidence: 92%

“…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%

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

240

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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“…54,58,59 When bone is subjected to loading, SOST expression and sclerostin levels decrease significantly, stimulating osteoblast activity and probably (through an effect on RANKL) inhibiting osteoclasts. 1,60,61 On the other hand, osteocytes have also recently been shown in vivo and in vitro to be the primary expressers of RANKL, a regulator of osteoclast differentiation and activation.…”

Section: Modeling: Evidence For and Implications In Acellular Bonementioning

confidence: 99%

The enigmas of bone without osteocytes

Shahar¹,

Dean²

2013

BoneKEy Reports

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One of the hallmarks of tetrapod bone is the presence of numerous cells (osteocytes) within the matrix. Osteocytes are vital components of tetrapod bone, orchestrating the processes of bone building, reshaping and repairing (modeling and remodeling), and probably also participating in calcium-phosphorus homeostasis via both the local process of osteocytic osteolysis, and systemic effect on the kidneys. Given these critical roles of osteocytes, it is thought-provoking that the entire skeleton of many fishes consists of bone material that does not contain osteocytes. This raises the intriguing question of how the skeleton of these animals accomplishes the various essential functions attributed to osteocytes in other vertebrates, and raises the possibility that in acellular bone some of these functions are either accomplished by non-osteocytic routes or not necessary at all. In this review, we outline evidence for and against the fact that primary functions normally ascribed to osteocytes, such as mechanosensation, regulation of osteoblast/clast activity and mineral metabolism, also occur in fish bone devoid of these cells, and therefore must be carried out through alternative and perhaps ancient pathways. To enable meaningful comparisons with mammalian bone, we suggest thorough, phylogenetic examinations of regulatory pathways, studies of structure and mechanical properties and surveys of the presence/absence of bone cells in fishes. Insights gained into the micro-/nanolevel structure and architecture of fish bone, its mechanical properties and its physiology in health and disease will contribute to the discipline of fish skeletal biology, but may also help answer questions of basic bone biology.

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Sclerostin Stimulates Osteocyte Support of Osteoclast Activity by a RANKL-Dependent Pathway

Cited by 456 publications

References 62 publications

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone

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

The enigmas of bone without osteocytes

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