美國研究人員13日在Developmental Cell發表封面文章，揭示了成熟成骨細 胞中Hedgehog（Hh）信號途徑在調節骨形成和骨吸收中的作用。 哺乳動物的骨組織中不斷發生骨形成和骨吸收兩個相反的過程，二者之間的 平衡受到嚴格控制，其穩態與骨骼質量密切相關。在體內，破骨細胞負責骨 吸收過程，成骨細胞負責骨形成過程。成骨細胞能夠分泌核因子NFκB配基的受 體激活因子（RANKL）和骨保護素（OPG）等因子，調節破骨細胞的分化。其 中RANKL能夠促進成骨細胞的分化，而OPG則是RANKL的誘捕受體，二者的比例 受到嚴格控制以維持骨質量。 Hh信號途徑在胚胎發育過程中對骨形成起重要的調節作用，但目前還不知道 它在已分化的成骨細胞內是否控制骨形成和重塑過程。美國的Mak等研究人員 發現，小鼠出生後隨著成骨細胞成熟，Hh信號途徑的活動性下降。選擇性上 調Hh信號途徑的強度，會引起骨形成的增加和過盛的骨吸收，導致突變老鼠 產生嚴重的骨質缺乏。相反地，抑制Hh信號通路能夠增加骨質量，並且能夠 減緩老年老鼠體內的骨質流失。 研究人員用定量RT-PCR技術、雙熒光素□檢測、Western印蹟和染色體免疫沉 澱等先進技術進一步研究了其細胞水平和分子水平的機制，結果表明，Hh信 號通過上調成骨細胞中副甲狀腺激素相關蛋白（PTHrP）的表達水平，進一步 通過蛋白激□A 和環腺□酸反應元件結合因子（CREB）促進RNAKL的表達，從 而間接增強破骨細胞的分化。 對不同年齡老鼠體內的基因表達進行檢測發現，隨年齡增加的骨質流失與Hh 信號的加強密切相關。通過控制Hh信號途徑調節骨形成和骨吸收過程，可能 能夠治療骨質疏鬆等疾病。 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 --

※ 發信站: 批踢踢實業坊(ptt.cc) ◆ From: 133.11.70.111