A peptidomimetic antagonist of the alpha(v)beta(3) integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo
A peptidomimetic antagonist of the alpha(v)beta(3) integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo
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DOI：
10.1172/jci119404
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发表时间：
1997-05-01
影响因子：
15.9
通讯作者：
Teitelbaum, SL
中科院分区：
文献类型：
--
作者：
Engelman, VW;Nickols, GA;Teitelbaum, SL
破骨细胞性骨降解需要基质和吸收细胞之间的亲密性。虽然整合素α(V)β(3)在这一过程中的确切作用尚不清楚，但通过可溶性配体或封闭抗体占据异二聚体在体内外有效地抑制骨吸收，提示αvβ(3)阻断可能预防绝经后骨质疏松症。因此。我们基于α(V)β(3)配体精氨酸-甘氨酸-天冬氨酸(beta-[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxopenthyl]amino-3-pyridinepropanoic)鉴定了一种人工合成的化学多肽模拟物Arg-Gly-Asp(SC56631)，它识别分离的整合素及其相关的α(V)β(5)，与天然多肽一样有效地抑制体外和体内的破骨细胞性骨吸收。最重要的是，静脉注射模拟物可以防止大鼠卵巢切除后6周内55%的骨小梁丢失，对SC56631治疗的去卵巢动物的骨组织学检查也证明了化合物的骨保留特性和减少破骨细胞数量的能力，因此，RGD模拟物防止了伴随雌激素停用而导致的快速骨丢失。
Osteoclastic bone degradation requires intimacy between the matrix and the resorptive cell. While the precise role the integrin alpha(v) beta(3) plays in the process is not yet understood, occupancy of the heterodimer by soluble ligand or by blocking antibody effectively inhibits bone resorption in vitro and in vivo, suggesting that alpha v beta(3) blockade may prevent postmenopausal osteoporosis. Thus. we identified a synthetic chemical peptide mimetic, beta-[2-[[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxopenthyl]amino-3-pyridinepropanoic acid, bistrifluoroacetate (SC56631) based upon the alpha(v) beta(3) ligand, Arg-Gly-Asp (RGD), which recognizes the isolated integrin, and its relative, alpha(v) beta(5), as effectively as does the natural peptide, The mimetic dampens osteoclastic bone resorption in vitro and in vivo. Most importantly, intravenous administration of the mimetic prevents the 55% loss of trabecular bone sustained by rats within 6 wk of oophorectomy, Histological examination of bones taken from SC56631-treated, oophorectomized animals also demonstrates the compound's bone sparing properties and its capacity to decrease osteoclast number, Thus, an RGD mimetic prevents the rapid bone loss that accompanies estrogen withdrawal.