The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization
The immune regulatory protein B7-H3 promotes osteoblast differentiation and bone mineralization
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DOI：
10.1073/pnas.0405259101
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发表时间：
2004-08-31
影响因子：
11.1
通讯作者：
Mak, TW
中科院分区：
文献类型：
--
作者：
Suh, WK;Wang, SX;Mak, TW
B7-H3是IG超家族蛋白质B7家族的成员，在抗原呈递细胞的表面上表达，并通过与T细胞上的未知反受体结合来下调T细胞功能。尽管B7-H3广泛表达，但其潜在的非免疫功能尚未得到解决。我们发现B7-H3在胚胎发生过程中在发育中的骨骼中高度表达，并且随着成骨细胞前体细胞分化成成熟的成骨细胞，其表达增加。当可溶性重组蛋白B7-H3-Fc中断B7-H3功能时，成骨细胞的体外骨形成受到抑制。对新生B7-H3基因敲除（KO）小鼠颅骨细胞的分析显示，成骨细胞前体细胞的数量正常，具有正常的增殖能力。然而，B7-H3缺陷的颅骨细胞表现出受损的成骨分化，导致体外矿化骨形成减少。这些结果表明，B7-H3是成骨细胞分化后期所必需的。尽管B7-H3 KO小鼠没有大体骨骼异常，但与WT对照组相比，它们在皮质骨（而非小梁骨）中显示出较低的骨矿物质密度。与骨矿物质密度降低一致，与WT小鼠相比，B7-H3 KO小鼠的股骨更容易骨折。综上所述，这些结果表明，B7-H3及其未知的反受体在骨形成中起着积极的调节作用。此外，我们的研究发现B7-H3是另一种在骨免疫界面中具有双重作用的分子。
B7-H3, a member of the B7 family of the Ig superfamily proteins, is expressed on the surface of the antigen-presenting cells and down-regulates T cell functions by engaging an unknown counterreceptor on T cells. Although B7-H3 is ubiquitously expressed, its potential nonimmune functions have not been addressed. We found that B7-H3 is highly expressed in developing bones during embryogenesis and that its expression increases as osteoblast precursor cells differentiate into mature osteoblasts. In vitro bone formation by osteoblastic cells was inhibited when B7-H3 function was interrupted by the soluble recombinant protein B7-H3-Fc. Analysis of calvarial cells derived from neonatal B7-H3 knockout (KO) mice revealed normal numbers of osteoblast precursor cells possessing a normal proliferative capacity. However, the B7-H3-deficient calvarial cells exhibited impaired osteogenic differentiation, resulting in decreased mineralized bone formation in vitro. These results suggest that B7-H3 is required for the later phase of osteoblast differentiation. Although B7-H3 KO mice had no gross skeletal abnormalities, they displayed a lower bone mineral density in cortical (but not trabecular) bones compared with WT controls. Consistent with the reduced bone mineral density, the femurs of B7-H3 KO mice were more susceptible to bone fracture compared with those of WT mice. Taken together, these results indicate that B7-H3 and its unknown counterreceptor play a positive regulatory role in bone formation. In addition, our findings identified B7-H3 as another molecule that has a dual role in the bone-immune interface.