Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, USA.
Bone. 2011 Jul;49(1):50-5. doi: 10.1016/j.bone.2010.08.008. Epub 2010 Aug 18.
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 prosurvival 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 p90(RSK) kinase and its substrates BAD and C/EBPβ, resulting in inhibition of apoptosis. The antiapoptotic effect of bisphosphonates is separate from the effect of the drugs on osteoclasts, as analogs that lack antiresorptive 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 anticatabolic actions, open new therapeutic possibilities for bisphosphonates in the treatment of osteopenic conditions in which decreased bone resorption is not desired.
双膦酸盐通过抑制破骨细胞的活性来阻止骨质流失。然而，双膦酸盐对骨量的影响并不能完全解释接受这些药物治疗的患者骨折发生率的降低。最近的研究工作通过证明双膦酸盐对骨骼的部分有益作用是由于防止成骨细胞和骨细胞凋亡来解释这种二分法。我们小组的工作，也得到了其他研究人员的独立证实，表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。这种促生存作用严格依赖于连接蛋白 (Cx) 43 的表达，这在体外使用缺乏 Cx43 的细胞或表达该蛋白的显性负突变体以及在体内使用 Cx43 成骨细胞/骨细胞特异性条件性敲除小鼠中得到了证实。值得注意的是，双膦酸盐对 Cx43 的这种依赖生存作用与间隙连接无关，而是来自 Cx43 半通道的开放。半通道的开放导致 Src 和细胞外信号调节激酶 (ERK) 的激酶激活，随后 ERK 细胞质靶标 p90(RSK) 激酶及其底物 BAD 和 C/EBPβ 的磷酸化，导致细胞凋亡的抑制。双膦酸盐的抗凋亡作用与药物对破骨细胞的作用分开，因为缺乏抗吸收活性的类似物仍然能够抑制体外成骨细胞和骨细胞的凋亡。此外，一种不抑制破骨细胞活性的双膦酸盐类似物能够预防糖皮质激素诱导的小鼠成骨细胞和骨细胞凋亡以及骨量和骨强度的丧失。成熟成骨细胞的成骨功能的保留和骨细胞网络的维持，结合缺乏抗分解代谢作用，为双膦酸盐在治疗不需要减少骨吸收的骨质疏松症方面开辟了新的治疗可能性。
