Essential Role of β-Catenin in Postnatal Bone Acquisition

Holmen, Sheri L.; Zylstra, Cassandra R.; Mukherjee, Aditi; Sigler, Robert E.; Faugère, Marie-Claude; Bouxsein, Mary L.; Deng, Lianfu; Clemens, Thomas L.; Williams, Bart O.

doi:10.1074/jbc.m501900200

Cited by 546 publications

(548 citation statements)

References 27 publications

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“…(32)(33)(34) To explore the potential role of b-catenin signaling in these gene changes, we assessed the temporal expression of total and phosphorylated b-catenin, and sclerostin, a well-characterized inhibitor of the pathway, on mouse and human bone sections. Immunohistochemical analysis of jck mouse bones demonstrates that the number of osteocytes expressing phosphorylated-Ser 33/37-b-catenin relative to total b-catenin is significantly increased in jck relative to WT mice and its expression is maintained throughout disease (Fig.…”

Section: Histomorphometric Analysis Reveals Early Bone Changes In Micementioning

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

234

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: Histomorphometric Analysis Reveals Early Bone Changes In Micementioning

confidence: 99%

Section: Introductionmentioning

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

234

224

View full text Add to dashboard Cite

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“…Inactivation of β-catenin in committed osteoblast progenitors prevented the expression of osteoblast-specific genes, indicating that β-catenin is also essential for osteoblast differentiation [15,16]. Mice with β-catenin removal in mature osteoblasts displayed severe osteopenia, which surprisingly was due to an increase in osteoclasts [17,18]. Normally, mature osteoblasts will secrete a RANKL decoy receptor, osteoprotegrin (OPG), to inhibit excess osteoclastogenesis [19].…”

Section: Introductionmentioning

confidence: 99%

“…Normally, mature osteoblasts will secrete a RANKL decoy receptor, osteoprotegrin (OPG), to inhibit excess osteoclastogenesis [19]. OPG is a Wnt responsive target gene and was found to be reduced in β-catenin −/− osteoblasts and upregulated in cells with hyperactive Wnt signaling [17,18,20]. Therefore the Wnt/β-catenin pathway directly controls multiple steps of osteoblast development, and indirectly controls osteoclast differentiation through OPG secreted from osteoblasts.…”

Section: Introductionmentioning

confidence: 99%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

156

106

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The Wnt/β-catenin signaling pathway has emerged as a key regulator in bone development and bone homeostasis. Loss-of-function mutations in the Wnt co-receptor LRP5 result in osteoporosis and "activating" mutations in LRP5 result in high bone mass. Dickkopf-1 (DKK1) is a secreted Wnt inhibitor that binds LRP5 and LRP6 during embryonic development, therefore it is expected that a decrease in DKK1 will result in an increase in Wnt activity and a high bone mass phenotype. Dkk1 −/− knockout mice are embryonic lethal, but mice with hypomorphic Dkk1 d (doubleridge) alleles that express low amounts of Dkk1 are viable. In this study we generated an allelic series by crossing Dkk1 +/− and Dkk1 +/d mice resulting in the following genotypes with decreasing Dkk1 expression levels: +/+, +/d, +/− and d/−. Using μCT imaging we scanned dissected left femora and calvariae from eight week old mice (n=60). We analyzed the distal femur to represent trabecular bone and the femur diaphysis for cortical endochondral bone. A region of the parietal bones was used to analyze intramembranous bone of the calvaria. We found that trabecular bone volume is increased in Dkk1 mutant mice in a manner that is inversely proportional to the level of Dkk1 expression. Trabeculae number and thickness were significantly higher in the low Dkk1 expressing genotypes from both female and male mice. Similar results were found in cortical bone with an increase in cortical thickness and cross sectional area of the femur diaphysis that correlated with lower Dkk1 expression. No consistent differences were found in the calvaria measurements. Our results indicate that the progressive Dkk1 reduction increases trabecular and cortical bone mass and that even a 25% reduction in Dkk1 expression could produce significant increases in trabecular bone volume fraction. Thus DKK1 is a negative regulator of normal bone homeostasis in vivo. Our study suggests that manipulation of DKK1 function or expression may have therapeutic significance for the treatment of low bone mass disorders.

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“…The process of osteoblast differentiation, and the subsequent repair of bone is driven by canonical Wingless (Wnt) signalling within the MSC (Cadigan and Nusse, 1997;Kikuchi, 2000;Huelsken and Birchmeier, 2001;Pandur et al, 2002;Bain et al, 2003;Rawadi et al, 2003;Bodine et al, 2004;Bennett et al, 2005;Gregory et al, 2005a, b;Holmen et al, 2005;Hartmann, 2006;Krishnan et al, 2006).…”

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confidence: 99%

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

et al. 2007

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Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3b inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immunodepletion of Dkk-1 or administration of GSK3b inhibitors could represent an adjunct therapy for this disease.

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Essential Role of β-Catenin in Postnatal Bone Acquisition

Cited by 546 publications

References 27 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

Bone mass is inversely proportional to Dkk1 levels in mice

A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

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