Osteoblastic responses to TGF-β during bone remodeling
Osteoblastic responses to TGF-β during bone remodeling
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DOI：
10.1091/mbc.9.7.1903
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发表时间：
1998-07-01
影响因子：
3.3
通讯作者：
Derynck, R
中科院分区：
文献类型：
--
作者：
Erlebacher, A;Filvaroff, EH;Derynck, R
骨重建依赖于成骨细胞骨形成和破骨细胞骨吸收的空间和时间耦合；然而，这些诱导相互作用的分子基础尚不清楚。我们之前已经证明，在转基因小鼠中，成骨细胞过度表达转化生长因子-β2可以解除骨重建的调节，并导致与年龄相关的骨量丢失，类似于人类的高周转率骨质疏松症。这种表型表明转化生长因子-β2是骨重建的生理调节因子，并提出了一个问题，即这种单一的分泌因子如何调节成骨细胞和破骨细胞的功能，并协调它们在体内的相反活动。为了深入了解转化生长因子-β在骨重建中的生理作用，我们现在表征了这些转基因小鼠中成骨细胞对转化生长因子-β的反应。我们利用了阿伦磷酸钠特异性抑制骨吸收的能力，c-fos(-/-)小鼠破骨细胞活性的缺乏，以及在成骨细胞中表达显性-阴性形式的II型转化生长因子-β受体的新转基因小鼠株系。我们的结果表明，转化生长因子-β直接提高了成骨细胞从成骨前体细胞向终末分化的成骨细胞的稳定期分化率，从而增加了植入骨基质中的骨细胞的最终密度。过度表达转化生长因子-β2的小鼠也有更高的骨基质形成率；然而，这种活性并不是转化生长因子-β对成骨细胞的直接影响，而更可能是对转化生长因子-β引起的骨吸收增加的动态平衡反应。最后，我们发现在骨吸收部位，破骨活性有助于转化生长因子-β诱导成骨细胞分化的增加。这些结果表明，转化生长因子-β是成骨细胞分化的生理调节因子，在骨重建过程中是骨形成与骨吸收耦合的中心成分。
Bone remodeling depends on the spatial and temporal coupling of bone formation by osteoblasts and bone resorption by osteoclasts; however, the molecular basis of these inductive interactions is unknown. We have previously shown that osteoblastic overexpression of TGF-beta 2 in transgenic mice deregulates bone remodeling and leads to an age-dependent loss of bone mass that resembles high-turnover osteoporosis in humans. This phenotype implicates TGF-beta 2 as a physiological regulator of bone remodeling and raises the question of how this single secreted factor regulates the functions of osteoblasts and osteoclasts and coordinates their opposing activities in vivo. To gain insight into the physiological role of TGF-beta in bone remodeling, we have now characterized the responses of osteoblasts to TGF-beta in these transgenic mice. We took advantage of the ability of alendronate to specifically inhibit bone resorption, the lack of osteoclast activity in c-fos(-/-) mice, and a new transgenic mouse line that expresses a dominant-negative form of the type II TGF-beta receptor in osteoblasts. Our results show that TGF-beta directly increases the steady-state rate of osteoblastic differentiation from osteoprogenitor cell to terminally differentiated osteocyte and thereby increases the final density of osteocytes embedded within bone matrix. Mice overexpressing TGF-beta 2 also have increased rates of bone matrix formation; however, this activity does not result from a direct effect of TGF-beta on osteoblasts, but is more likely a homeostatic response to the increase in bone resorption caused by TGF-beta. Lastly, we find that osteoclastic activity contributes to the TGF-beta-induced increase in osteoblast differentiation at sites of bone resorption. These results suggest that TGF-beta is a physiological regulator of osteoblast differentiation and acts as a central component of the coupling of bone formation to resorption during bone remodeling.