Transforming growth factor β affects osteoclast differentiation via direct and indirect actions
Transforming growth factor β affects osteoclast differentiation via direct and indirect actions
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DOI：
10.1359/jbmr.2001.16.10.1787
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发表时间：
2001-10-01
影响因子：
6.2
通讯作者：
Gillespie, MT
中科院分区：
文献类型：
--
作者：
Quinn, JMW;Itoh, K;Gillespie, MT
转化生长因子β (tgf - β)在骨中含量丰富，对骨溶解有复杂的影响，对破骨细胞分化有积极和消极的影响，表明其作用机制不止一种。破骨细胞的发生主要是由成骨细胞（OB）表达肿瘤坏死因子（TNF）相关分子受体激活因子nf - κ b配体（RANKL）及其诱饵受体骨保护素（OPG）决定的，它们分别受溶骨因子的升高和降低。一种由tnf - α介导的不依赖rankl的破骨细胞形成机制也已被证实。因此，我们研究了tgf - β对破骨细胞形成的影响，其中破骨细胞刺激依赖于ob和由外源性添加RANKL或tnf - α提供的培养系统。OPG和tgf - β均抑制造血细胞/OB共培养中破骨细胞的形成，但其作用动力学不同。tgf - β也抑制来自OPG null（-/-）小鼠的细胞共培养的破骨细胞生成。TGF- β强烈降低了培养成骨细胞中RANKL信使RNA （mRNA）的表达，在TGF- β中添加外源RANKL抑制了opg（-/-）细胞的共培养，部分恢复了破骨细胞的发生。综上所述，这些数据表明tgf - β的抑制作用主要是通过减少RANKL的OB产生来介导的。相反，在没有OBs的情况下，tgf - β大大增加了重组RANKL或tnf - α刺激培养的造血细胞或RAW 264.7巨噬细胞样细胞中破骨细胞的形成，其水平比RANKL或tnf - α最大刺激所能达到的水平高出数倍。这些数据表明tgf - β可能通过作用于破骨细胞前体而增加破骨细胞的形成。因此，尽管RANKL（或tnf - α）对破骨细胞的形成至关重要，但tgf - β等因子可能会有力地改变这些破骨细胞刺激。这些作用可能对生理性和病理生理性骨溶解的控制至关重要。
Transforming growth factor beta (TGF-beta) is abundant in bone and has complex effects on osteolysis, with both positive and negative effects on osteoclast differentiation, suggesting that it acts via more than one mechanism. Osteoclastogenesis is determined primarily by osteoblast (OB) expression of the tumor necrosis factor (TNF)-related molecule receptor activator of NF-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG), which are increased and decreased, respectively, by osteolytic factors. A RANKL-independent osteoclastogenic mechanism mediated by TNF-alpha has also been shown. Therefore, we investigated TGF-beta effects on osteoclast formation in culture systems in which osteoclastogenic stimulus is dependent on OBs and culture systems where it was provided by exogenously added RANKL or TNF-alpha. Both OPG and TGF-beta inhibited osteoclast formation in hemopoietic cell/OB cocultures, but the kinetics of their action differed. TGF-beta also inhibited osteoclastogenesis in cocultures of cells derived from OPG null (opg(-/-)) mice. TGF-beta strongly decreased RANKL messenger RNA (mRNA) expression in cultured osteoblasts, and addition of exogenous RANKL to TGF beta -inhibited cocultures of opg(-/-) cells partially restored osteoclastogenesis. Combined, these data indicate that the inhibitory actions of TGF-beta were mediated mainly by decreased OB production of RANKL. In contrast, in the absence of OBs, TGF-beta greatly increased osteoclast formation in recombinant RANKL- or TNF-alpha -stimulated cultures of hemopoietic cells or RAW 264.7 macrophage-like cells to levels several-fold greater than attainable by maximal stimulation by RANKL or TNF-alpha. These data suggest that TGF-beta may increase osteoclast formation via action on osteoclast precursors. Therefore, although RANKL (or TNF-alpha) is essential for osteoclast formation, factors such as TGF-beta may powerfully modify these osteoclastogenic stimuli. Such actions may be critical to the control of physiological and pathophysiological osteolysis.