Regulation of osteoblastogenesis and bone mass by Wnt10b
Regulation of osteoblastogenesis and bone mass by Wnt10b
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DOI：
10.1073/pnas.0408742102
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发表时间：
2005-03-01
影响因子：
11.1
通讯作者：
MacDougald, OA
中科院分区：
文献类型：
--
作者：
Bennett, CN;Longo, KA;MacDougald, OA
令状由一系列分泌的信号蛋白组成，这些蛋白调节着不同的发育过程。WNT10b激活WRIT信号可抑制前脂肪细胞的分化，阻碍脂肪组织的发育；然而，WNT10b对其他间充质系的作用尚不明确。为了探讨WRIT信号在骨发育中的生理作用，我们分析了在骨髓中表达WNT10b基因的FABP4-WNT10b小鼠。来自FABP4-WNT10b小鼠的股骨在远端干骺端有几乎四倍的骨量，并且机械强度更高。这些小鼠至少在23个月大的时候保持高骨量。此外，FABP4-Wnt10b小鼠可免受雌激素缺乏所特有的骨质丢失的影响。我们用药理学和遗传学的方法证明了规范的Wnt信号刺激成骨细胞的生成和抑制双潜能间充质前体的脂肪生成。WNT10b通过诱导成骨细胞转录因子Runx2、DIx5和Osterix，以及抑制成脂转录因子C/EBPalpha和PPARGamma，将细胞命运转向成骨细胞谱系。WNT10b促进成骨细胞形成的一个机制是抑制PPARγ的表达。最后，Wnt10b-/-小鼠的骨小梁和血清骨钙素水平降低，证实Wnt10b是骨形成的内源性调节因子。
Writs comprise a family of secreted signaling proteins that regulate diverse developmental processes. Activation of Writ 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 Writ 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, DIx5, and osterix and suppression of the adipogenic transcription factors C/EBPalpha and PPARgamma. One mechanism whereby Wnt10b promotes osteoblastogenesis is suppression of PPARgamma expression. Finally, Wnt10b-/- mice have decreased trabecular bone and serum osteocalcin, confirming that Wnt10b is an endogenous regulator of bone formation.