Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model.
Sclerostin antibody treatment improves fracture outcomes in a Type I diabetic mouse model.
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DOI：
10.1016/j.bone.2015.04.048
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发表时间：
2016-01
期刊：
影响因子：
4.1
通讯作者：
Collette NM
中科院分区：
文献类型：
--
作者：
Yee CS;Xie L;Hatsell S;Hum N;Murugesh D;Economides AN;Loots GG;Collette NM
1型糖尿病(T1 DM)患者由于成骨细胞活性降低而出现骨量减少和骨折愈合障碍。此外，目前还没有足够的治疗方法可以恢复T1 DM患者受损的愈合；因此，迫切需要研究治疗骨科并发症的新疗法。硬化素是一种WNT拮抗剂，对骨形成有负性调节作用，而SostAb是一种有效的骨合成代谢药。为了确定SOST抗体(SostAb)治疗是否促进链脲佐菌素(STZ)诱导的T1 DM小鼠的骨折愈合，我们在骨折后21天每周两次注射SostAb，并在骨折后21天和42天(分别为11周和14周)检测骨质量和骨痂结果。在这里，我们显示SostAb治疗改善了骨参数；这些改善在抗体治疗停止后持续存在。成骨细胞分化标志物RUNX2、I型胶原、骨钙素、DMP1减少，骨痂表面可见大量SP7/Osterix阳性的早期成骨细胞。这些结果表明，STZ骨痂由于成骨细胞不能充分分化和产生矿化基质而成骨能力较差，从而产生矿化骨痂较少。SostAb治疗促进了正常组和STZ组的骨折愈合，在STZ+SostAb组小鼠中，也逆转了STZ骨痂中的低矿化程度。骨痂的显微CT分析显示，SostAb治疗改善了骨参数，矿化骨与对照组相当。此外，我们还发现，在STZ小鼠中，硬化素水平升高，β-连环蛋白活性降低。与其作为WnT拮抗剂的功能一致，SostAb处理提高了β-连环蛋白的活性，但也增加了愈伤组织和循环中的SOST水平。我们的结果表明，SostAb治疗通过促进成骨细胞分化和骨矿化，挽救了STZ诱导的T1 DM骨折模型中受损的成骨细胞。
Type 1 diabetes mellitus (T1DM) patients have osteopenia and impaired fracture healing due to decreased osteoblast activity. Further, no adequate treatments are currently available that can restore impaired healing in T1DM; hence a significant need exists to investigate new therapeutics for treatment of orthopedic complications. Sclerostin (SOST), a WNT antagonist, negatively regulates bone formation, and SostAb is a potent bone anabolic agent. To determine whether SOST antibody (SostAb) treatment improves fracture healing in streptozotocin (STZ) induced T1DM mice, we administered SostAb twice weekly for up to 21 days post-fracture, and examined bone quality and callus outcomes at 21 days and 42 days post fracture (11 and 14 weeks of age, respectively). Here we show that SostAb treatment improves bone parameters; these improvements persist after cessation of antibody treatment. Markers of osteoblast differentiation such as RUNX2, collagen I, osteocalcin, and DMP1 were reduced, while an abundant number of SP7/osterix-positive early osteoblasts were observed on the bone surface of STZ calluses. These results suggest that STZ calluses have poor osteogenesis resulting from failure of osteoblasts to fully differentiate and produce mineralized matrix, which produces a less mineralized callus. SostAb treatment enhanced fracture healing in both normal and STZ groups, and in STZ+SostAb mice, also reversed the lower mineralization seen in STZ calluses. Micro-CT analysis of calluses revealed improved bone parameters with SostAb treatment, and the mineralized bone was comparable to Controls. Additionally, we found sclerostin levels to be elevated in STZ mice and β-catenin activity to be reduced. Consistent with its function as a WNT antagonist, SostAb treatment enhanced β-catenin activity, but also increased the levels of SOST in the callus and in circulation. Our results indicate that SostAb treatment rescues the impaired osteogenesis seen in the STZ induced T1DM fracture model by facilitating osteoblast differentiation and mineralization of bone.