Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression
Osteopontin deficiency produces osteoclast dysfunction due to reduced CD44 surface expression
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DOI：
10.1091/mbc.e02-06-0354
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发表时间：
2003-01-01
影响因子：
3.3
通讯作者：
Hruska, KA
中科院分区：
文献类型：
--
作者：
Chellaiah, MA;Kizer, N;Hruska, KA
骨桥蛋白(OPN)在小鼠野生型破骨细胞中表达，定位于基底外侧、透明带和褶皱的边缘膜，并在骨吸收过程中沉积在吸收陷窝中。体外培养的禽类破骨细胞缺乏OPN分泌进入吸收湾，可能是其功能性吸收缺陷的原因之一。OPN缺乏的破骨细胞在体外表现为低运动性和骨吸收能力降低。OPN刺激破骨细胞表面CD44的表达，CD44被证明是破骨细胞运动和骨吸收所必需的。在OPN-/-破骨细胞中加入外源性OPN可增加CD44的表面表达，并通过激活α(V)β(3)整合素挽救破骨细胞运动。外源性OPN只能部分恢复骨吸收，因为加入OPN不能像野生型破骨细胞那样将OPN分泌到吸收槽中。正如这些破骨细胞功能障碍的体外发现所预期的那样，在OPN缺陷的小鼠中，一种迄今未被认识的骨表型具有特征。在从OPN缺陷小鼠分离的胫骨的组织形态计量学测量中，观察到尽管破骨细胞数量增加，干骺端小梁的骨吸收延迟和侵蚀周长减少。组织形态计量学的发现与股骨负荷-失效测试显示的骨骼刚性和转动惯量的增加有关。这些发现证明了OPN在破骨细胞功能中的作用，以及在骨重建过程中OPN作为破骨细胞自分泌因子的必要性。
Osteopontin (OPN) was expressed in murine wild-type osteoclasts, localized to the basolateral, clear zone, and ruffled border membranes, and deposited in the resorption pits during bone resorption. The lack of OPN secretion into the resorption bay of avian osteoclasts may be a component of their functional resorption deficiency in vitro. Osteoclasts deficient in OPN were hypomotile and exhibited decreased capacity for bone resorption in vitro. OPN stimulated CD44 expression on the osteoclast surface, and CD44 was shown to be required for osteoclast motility and bone resorption. Exogenous addition of OPN to OPN-/- osteoclasts increased the surface expression of CD44, and it rescued osteoclast motility due to activation of the alpha(v)beta(3) integrin. Exogenous OPN only partially restored bone resorption because addition of OPN failed to produce OPN secretion into resorption bays as seen in wild-type osteoclasts. As expected with these in vitro findings of osteoclast dysfunction, a bone phenotype, heretofore unappreciated, was characterized in OPN-deficient mice. Delayed bone resorption in metaphyseal trabeculae and diminished eroded perimeters despite an increase in osteoclast number were observed in histomorphometric measurements of tibiae isolated from OPN-deficient mice. The histomorphometric findings correlated with an increase in bone rigidity and moment of inertia revealed by load-to-failure testing of femurs. These findings demonstrate the role of OPN in osteoclast function and the requirement for OPN as an osteoclast autocrine factor during bone remodeling.