美国研究人员13日在Developmental Cell发表封面文章，揭示了成熟成骨细 胞中Hedgehog（Hh）信号途径在调节骨形成和骨吸收中的作用。 哺乳动物的骨组织中不断发生骨形成和骨吸收两个相反的过程，二者之间的 平衡受到严格控制，其稳态与骨骼质量密切相关。在体内，破骨细胞负责骨 吸收过程，成骨细胞负责骨形成过程。成骨细胞能够分泌核因子NFκB配基的受 体激活因子（RANKL）和骨保护素（OPG）等因子，调节破骨细胞的分化。其 中RANKL能够促进成骨细胞的分化，而OPG则是RANKL的诱捕受体，二者的比例 受到严格控制以维持骨质量。 Hh信号途径在胚胎发育过程中对骨形成起重要的调节作用，但目前还不知道 它在已分化的成骨细胞内是否控制骨形成和重塑过程。美国的Mak等研究人员 发现，小鼠出生後随着成骨细胞成熟，Hh信号途径的活动性下降。选择性上 调Hh信号途径的强度，会引起骨形成的增加和过盛的骨吸收，导致突变老鼠 产生严重的骨质缺乏。相反地，抑制Hh信号通路能够增加骨质量，并且能够 减缓老年老鼠体内的骨质流失。 研究人员用定量RT-PCR技术、双荧光素□检测、Western印蹟和染色体免疫沉 淀等先进技术进一步研究了其细胞水平和分子水平的机制，结果表明，Hh信 号通过上调成骨细胞中副甲状腺激素相关蛋白（PTHrP）的表达水平，进一步 通过蛋白激□A 和环腺□酸反应元件结合因子（CREB）促进RNAKL的表达，从 而间接增强破骨细胞的分化。 对不同年龄老鼠体内的基因表达进行检测发现，随年龄增加的骨质流失与Hh 信号的加强密切相关。通过控制Hh信号途径调节骨形成和骨吸收过程，可能 能够治疗骨质疏松等疾病。 Developmental Cell，Vol 14, 674-688 Hedgehog Signaling in Mature Osteoblasts Regulates Bone Formation and Resorption by Controlling PTHrP and RANKL Expression 摘要 Hedgehog (Hh) signaling is required for osteoblast differentiation from mesenchymal progenitors during endochondral bone formation. However, the role of Hh signaling in differentiated osteoblasts during adult bone homeostasis remains to be elucidated. We found that in the postnatal bone, Hh signaling activity was progressively reduced as osteoblasts mature. Upregulating Hh signaling selectively in mature osteoblasts led to increased bone formation and excessive bone resorption. As a consequence, these mutant mice showed severe osteopenia. Conversely, inhibition of Hh signaling in mature osteoblasts resulted in increased bone mass and protection from bone loss in older mice. Cellular and molecular studies showed that Hh signaling indirectly induced osteoclast differentiation by upregulating osteoblast expression of PTHrP, which promoted RANKL expression via PKA and its target transcription factor CREB. Our results demonstrate that Hh signaling in mature osteoblasts regulates both bone formation and resorption and that inhibition of Hh signaling reduces bone loss in aged mice. http://www.bioon.com/biology/cell/370290.shtml --

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