Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability.
Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability.
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DOI：
10.1016/j.bone.2010.08.008
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发表时间：
2011-07
期刊：
影响因子：
4.1
通讯作者：
Plotkin, Lilian I.
中科院分区：
文献类型：
--
作者：
Bellido, Teresita;Plotkin, Lilian I.
双膦酸盐通过抑制骨吸收破骨细胞的活性来阻止骨丢失。然而，双膦酸盐对骨量的影响不能完全解释在接受这些药物治疗的患者中观察到的骨折发生率降低。最近的研究工作通过证明双膦酸盐对骨骼的有益作用的一部分是由于预防成骨细胞和骨细胞凋亡而对这种二分法提供了解释。我们小组的工作，由其他研究人员独立证实，证明双膦酸盐能够在体外和体内防止成骨细胞和骨细胞凋亡。这种促存活作用严格依赖于连接蛋白（Cx）43的表达，如使用缺乏Cx 43或表达该蛋白的显性阴性突变体的细胞在体外以及使用Cx 43成骨细胞/骨细胞特异性条件性敲除小鼠在体内所证明的。值得注意的是，这种Cx43依赖的生存效果的二膦酸盐是独立的缝隙连接和结果的Cx43半通道的开放。半通道开放导致激酶Src和细胞外信号调节激酶（ERK）活化，随后ERK胞质靶点p90 RSK激酶及其底物BAD和C/EBPβ磷酸化，导致细胞凋亡抑制。双膦酸盐的抗凋亡作用与药物对破骨细胞的作用是分开的，因为缺乏抗再吸收活性的类似物仍然能够在体外抑制成骨细胞和骨细胞凋亡。此外，不抑制破骨细胞活性的双膦酸盐类似物可防止小鼠中糖皮质激素诱导的成骨细胞和骨细胞凋亡以及骨量和强度的损失。成熟成骨细胞的骨形成功能的保留和骨细胞网络的维持，与缺乏抗分解代谢作用相结合，为双膦酸盐在治疗其中不希望降低骨吸收的骨质减少病症中开辟了新的治疗可能性。
Bisphosphonates stop bone loss by inhibiting the activity of bone resorbing osteoclasts. However, the effect of bisphosphonates on bone mass cannot completely explain the reduction in fracture incidence observed in patients treated with these agents. Recent research efforts provided an explanation to this dichotomy by demonstrating that part of the beneficial effect of bisphosphonates on the skeleton is due to prevention of osteoblast and osteocyte apoptosis. Work of our group, independently confirmed by other investigators, demonstrated that bisphosphonates are able to prevent osteoblast and osteocyte apoptosis in vitro and in vivo. This pro-survival effect is strictly dependent on the expression of connexin (Cx)43, as demonstrated in vitro using cells lacking Cx43 or expressing dominant negative mutants of the protein as well as in vivo using Cx43 osteoblast/osteocyte-specific conditional knock-out mice. Remarkably, this Cx43-dependent survival effect of bisphosphonates is independent of gap junctions and results from opening of Cx43 hemichannels. Hemichannel opening leads to activation of the kinases Src and extracellular signal-regulated kinases (ERKs), followed by phosphorylation of the ERK cytoplasmic target p90RSK kinase and its substrates BAD and C/EBPβ, resulting in inhibition of apoptosis. The anti-apoptotic effect of bisphosphonates is separate from the effect of the drugs on osteoclasts, as analogs that lack anti-resorptive activity are still able to inhibit osteoblast and osteocyte apoptosis in vitro. Furthermore, a bisphosphonate analog that does not inhibit osteoclast activity prevented osteoblast and osteocyte apoptosis and the loss of bone mass and strength induced by glucocorticoids in mice. Preservation of the bone forming function of mature osteoblasts and maintenance of the osteocytic network, in combination with lack anti-catabolic actions, open new therapeutic possibilities for bisphosphonates in the treatment of osteopenic conditions in which decreased bone resorption is not desired.
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