生物谷報(bào)道：美國研究人員13日在Developmental Cell發(fā)表封面文章，揭示了成熟成骨細(xì)胞中Hedgehog（Hh）信號途徑在調(diào)節(jié)骨形成和骨吸收中的作用,。
哺乳動(dòng)物的骨組織中不斷發(fā)生骨形成和骨吸收兩個(gè)相反的過程,，二者之間的平衡受到嚴(yán)格控制，其穩(wěn)態(tài)與骨骼質(zhì)量密切相關(guān),。在體內(nèi),，破骨細(xì)胞負(fù)責(zé)骨吸收過程，成骨細(xì)胞負(fù)責(zé)骨形成過程,。成骨細(xì)胞能夠分泌核因子NFκB配基的受體激活因子（RANKL）和骨保護(hù)素（OPG）等因子,，調(diào)節(jié)破骨細(xì)胞的分化,。其中RANKL能夠促進(jìn)成骨細(xì)胞的分化,，而OPG則是RANKL的誘捕受體，二者的比例受到嚴(yán)格控制以維持骨質(zhì)量,。
Hh信號途徑在胚胎發(fā)育過程中對骨形成起重要的調(diào)節(jié)作用,，但目前還不知道它在已分化的成骨細(xì)胞內(nèi)是否控制骨形成和重塑過程。美國的Mak等研究人員發(fā)現(xiàn),，小鼠出生后隨著成骨細(xì)胞成熟,，Hh信號途徑的活動(dòng)性下降。選擇性上調(diào)Hh信號途徑的強(qiáng)度,，會(huì)引起骨形成的增加和過盛的骨吸收,，導(dǎo)致突變老鼠產(chǎn)生嚴(yán)重的骨質(zhì)缺乏。相反地,，抑制Hh信號通路能夠增加骨質(zhì)量,，并且能夠減緩老年老鼠體內(nèi)的骨質(zhì)流失。
研究人員用定量RT-PCR技術(shù),、雙熒光素酶檢測,、Western印跡和染色體免疫沉淀等先進(jìn)技術(shù)進(jìn)一步研究了其細(xì)胞水平和分子水平的機(jī)制，結(jié)果表明,，Hh信號通過上調(diào)成骨細(xì)胞中副甲狀腺激素相關(guān)蛋白（PTHrP）的表達(dá)水平,，進(jìn)一步通過蛋白激酶A 和環(huán)腺苷酸反應(yīng)元件結(jié)合因子（CREB）促進(jìn)RNAKL的表達(dá)，從而間接增強(qiáng)破骨細(xì)胞的分化,。
對不同年齡老鼠體內(nèi)的基因表達(dá)進(jìn)行檢測發(fā)現(xiàn),，隨年齡增加的骨質(zhì)流失與Hh信號的加強(qiáng)密切相關(guān)。通過控制Hh信號途徑調(diào)節(jié)骨形成和骨吸收過程,，可能能夠治療骨質(zhì)疏松等疾病,。（生物谷www.bioon.com）
生物谷推薦原始出處：
Developmental Cell，Vol 14, 674-688, 13 May 2008,，Kinglun Kingston Mak, Yingzi Yang
Hedgehog Signaling in Mature Osteoblasts Regulates Bone Formation and Resorption by Controlling PTHrP and RANKL Expression
Kinglun Kingston Mak,1 Yanming Bi,2 Chao Wan,3 Pao-Tien Chuang,4 Thomas Clemens,3 Marian Young,2 and Yingzi Yang1,
1 Genetic Disease Research Branch, National Human Genome Research Institute, Bethesda, MD 20892, USA
2 Craniofacial and Skeletal Diseases Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA
3 Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, 1670 University Boulevard, VH G001, Birmingham, AL 35294-0019, USA
4 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
Summary
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.
