The Wnt Antagonist Secreted Frizzled-Related Protein-1 Is a Negative Regulator of Trabecular Bone Formation in Adult Mice

Bodine, Peter V.N.; Zhao, Weiguang; Kharode, Yogendra; Bex, Frederick J.; Lambert, Andre-Jean; Goad, Mary Beth; Gaur, Tripti; Stein, Gary S.; Lian, Jane B.; Komm, Barry S.

doi:10.1210/me.2003-0498

Cited by 422 publications

(415 citation statements)

References 42 publications

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“…(18,19) Despite this controversy, there is in vivo evidence for a negative regulation of bone formation by Wnt antagonists such as DKK1, Krm2, or Sfrp1. (20)(21)(22)(23) These observations supported the existence of an in vivo cell autonomous effect of Wnts in osteoblasts. The role of Wnt signaling in controlling preosteoblastic cell proliferation and differentiation is not clear.…”

Section: Introductionsupporting

confidence: 69%

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

Caverzasio

Thouverey

2012

Journal of Bone and Mineral Research

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Previous studies have shown that Wnt3a enhances the proliferation and inhibits the osteogenic differentiation of human mesenchymal stem cells (hMSCs). In this study, we investigated the signaling pathways involved in Wnt3a-induced osteoblastic cell proliferation. Experiments with DKK1, a natural antagonist of Lrp5/6, indicated that Wnt/b-catenin did not play a major role in Wnt3a-induced osteoblastic cell proliferation. The use of selective inhibitors of known mitogenic pathways implicates Src family kinases (SFKs) and a protein kinase C (PKC) in this cellular response. Time-dependent analysis of signaling molecules activated by Wnt3a in MC3T3-E1 cells revealed parallel activation of the canonical pathway and of several tyrosine kinases, including SFKs and PDGF receptors (PDGF-Rs). Functional analysis with specific inhibitors suggested a major role of PDGF-Rs in mediating Wnt3a-induced cell proliferation. Further investigation with an si-RNA approach confirmed a predominant role of this receptor in this cellular response. The use of soluble decoy PDGF-Rs that can sequester extracellular PDGFs excluding that part of the increased PDGF receptor phosphorylation by Wnt3a was the result of autocrine production of PDGFs. A selective SFK inhibitor blunted the enhanced PDGF-R phosphorylation and cell proliferation induced by Wnt3a. Studies of initial events involved in the regulation of this pathway suggest a role of dishevelled. In conclusion, data presented in this study indicate that cell proliferation induced by Wnt3a in osteoblastic cells is mediated by a dishevelleddependent and b-catenin-independent pathway, which involves the transactivation of PDGF receptors. ß

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Section: Introductionsupporting

confidence: 69%

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

Caverzasio

Thouverey

2012

Journal of Bone and Mineral Research

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“…Alteration of several intracellular and extracellular controllers of the levels of transduced Wnt/b-catenin signaling has indeed been linked to disturbed skeletal homeostasis. (30)(31)(32)(33)(34) Using murine conditional genetic models, we and others have shown that Apc is involved in the regulation of both prenatal and postnatal bone mass accrual by regulating the levels of Wnt/b-catenin signalling. (11,12) This study confirms findings from these in vivo animal studies by demonstrating that heterozygous mutations in the APC gene are associated with a higher than normal bone mass in a majority of FAP patients.…”

Section: Discussionmentioning

confidence: 99%

APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

Miclea

Karperien

Langers

et al. 2010

Journal of Bone and Mineral Research

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The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, bcatenin. Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of b-catenin turnover, and heterozygous germline mutations in the APC gene cause familial adenomatous polyposis (FAP). Whether APC mutations affect bone mass has not been previously investigated. We conducted a cross-sectional study evaluating skeletal status in FAP patients with a documented APC mutation. Twenty-two FAP patients with a mean age of 42 years (54.5% women) were included in this study. Mean bone mineral density (BMD) Z-scores were significantly increased above normal at all measured sites: lumbar spine (p < .01), total hip (p < .01), femoral neck (p < .05), and trochanter (p < .01). Z-scores were þ1 or greater in 14 patients (63.6%) and þ2 or greater in 5 (22.7%). Mean values of bone turnover markers were within normal ranges. There was a significant positive correlation between procollagen type I N-terminal propeptide (P1NP) and b-crosslaps (b-CTX) (r ¼ 0.70, p < .001) and between these markers and sclerostin and BMD measurements. We demonstrate that FAP patients display a significantly higher than normal mean BMD compared with age-and sex-matched healthy controls in the presence of a balanced bone turnover. Our data suggest a state of ''controlled'' activation of the Wnt signaling pathway in heterozygous carriers of APC mutations, most likely owing to upregulation of cytoplasmic b-catenin levels. ß

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“…Consistent with the removal of a Wnt inhibitor, the mouse knockout for Sfrp1 −/− displays an increase in trabecular bone mass in adult animals [22]. Previously identified as a BMP antagonist, SOST also binds to LRP5 and LRP6 in the extracellular region and antagonizes Wnt signaling [23,24].…”

Section: Introductionmentioning

confidence: 86%

Bone mass is inversely proportional to Dkk1 levels in mice

MacDonald

Joiner

Oyserman

et al. 2007

Bone

158

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 Wnt Antagonist Secreted Frizzled-Related Protein-1 Is a Negative Regulator of Trabecular Bone Formation in Adult Mice

Cited by 422 publications

References 42 publications

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

Predominant role of PDGF receptor transactivation in Wnt3a-induced osteoblastic cell proliferation

APC mutations are associated with increased bone mineral density in patients with familial adenomatous polyposis

Bone mass is inversely proportional to Dkk1 levels in mice

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