Regulation of osteoblastogenesis and bone mass by Wnt10b

Abstract

Wnts comprise a family of secreted signaling proteins that regulate diverse developmental processes. Activation of Wnt signaling by Wnt10b inhibits differentiation of preadipocytes and blocks adipose tissue development; however, the effect of Wnt10b on other mesenchymal lineages has not been defined. To explore the physiological role of Wnt signaling in bone development, we analyzed FABP4-Wnt10b mice, which express the Wnt10b transgene in marrow. Femurs from FABP4-Wnt10b mice have almost four times as much bone in the distal metaphyses and are mechanically stronger. These mice maintain elevated bone mass at least through 23 months of age. In addition, FABP4-Wnt10b mice are protected from the bone loss characteristic of estrogen deficiency. We used pharmacological and genetic approaches to demonstrate that canonical Wnt signaling stimulates osteoblastogenesis and inhibits adipogenesis of bipotential mesenchymal precursors. Wnt10b shifts cell fate toward the osteoblast lineage by induction of the osteoblastogenic transcription factors Runx2, Dlx5, and osterix and suppression of the adipogenic transcription factors C͞EBP␣ and PPAR␥. One mechanism whereby Wnt10b promotes osteoblastogenesis is suppression of PPAR␥ expression. Finally, Wnt10b؊͞؊ mice have decreased trabecular bone and serum osteocalcin, confirming that Wnt10b is an endogenous regulator of bone formation.adipogenesis ͉ development ͉ stem cells M esenchymal progenitors can differentiate into a number of cell types, including adipocytes and osteoblasts (1). One factor that regulates the reciprocal relationship between these lineages is Wnt signaling, which inhibits adipogenesis and stimulates osteoblastogenesis. Activation of Wnt signaling blocks preadipocyte differentiation by inhibiting expression of the adipogenic transcription factors C͞EBP␣ and PPAR␥ (2-5). The endogenous inhibitory Wnt signal may be initiated by Wnt10b, which is expressed in preadipocytes and stromal vascular cells but not in adipocytes (2, 3). Expression of Wnt10b from the FABP4 promoter decreases accumulation of white adipose tissue by Ϸ50% and completely blocks the development of brown fat (6, 7). Furthermore, FABP4-Wnt10b mice resist diet-induced obesity and the associated glucose intolerance.The first indication that Wnt signaling plays a critical role in bone formation came from human studies where inactivating mutations in the Wnt coreceptor LRP5 were shown to cause osteoporosis (8). These findings were supported by the observation that LRP5Ϫ͞Ϫ mice also have low bone mass (9). Furthermore, gain-of-function mutations in LRP5 that increase Wnt signaling result in higher bone density in humans and mice (10,11). Consistent with the effects of LRP5 on bone mass being mediated through canonical Wnt signaling, activation of this pathway in vitro results in the expression of alkaline phosphatase, an early osteoblast marker (12)(13)(14). Although these and other studies suggest that endogenous Wnt signaling regulates osteoblastogenesis and bone formation (15), a specific Wnt or Wnts...

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