Sclerostin antibody prevented progressive bone loss in combined ovariectomized and concurrent functional disuse.
Sclerostin antibody prevented progressive bone loss in combined ovariectomized and concurrent functional disuse.
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DOI：
10.1016/j.bone.2016.02.005
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发表时间：
2016-06
期刊：
影响因子：
4.1
通讯作者：
Qin YX
中科院分区：
文献类型：
--
作者：
Zhang D;Hu M;Chu T;Lin L;Wang J;Li X;Ke HZ;Qin YX
骨质疏松症以骨量减少和骨小梁结构受损为特征，常见于绝经后雌激素缺乏的女性。此外，长时间的机械卸载，即长期卧床休息，可能会加剧骨丢失。硬化素是一种Wnt信号拮抗剂，对骨形成起负性调节作用。一种硬化素中和抗体(scl-Ab)增加了绝经后骨质疏松症女性和健康男性的骨密度。本研究的目的是观察去卵巢(OVX)同时机械卸载大鼠骨丢失的情况，并评价硬化素抗体治疗对该模型中可能出现的严重骨丢失的缓解作用。本研究选用4月龄去卵巢或假手术的雌性SD大鼠。抵达后2天，采用后肢悬吊(HLS)或免费救护车的方法进行功能性废用。从HLS开始，每周两次皮下注射赋形剂或scl-Ab25 mg/kg，共5周。μCT分析显示，HLS型、OVX型和HLS型+OVX型患者远端干骺端骨小梁结构完整性显著降低(骨体积分数分别减少29%、71%和87%)。与安慰剂组相比，scl-Ab组的各项骨小梁参数(骨体积分数分别增加111%、229%和297%)显著改善，组织形态计量学显示，其力学性能增强，骨形成增加。上述结果提示，Scl-Ab可预防去卵巢大鼠同时机械卸载后松质骨量和皮质骨强度的丢失。结果提示，单抗是治疗雌激素缺乏并发机械负荷所致严重骨质疏松症的一种有前景的治疗方法。
Osteoporosis is characterized by low bone mass and compromised trabecular architecture, and is commonly occurred in post-menopausal women with estrogen deficiency. In addition, prolonged mechanical unloading, i.e., long term bed rest, can exaggerate the bone loss. Sclerostin is a Wnt signaling antagonist and acts as a negative regulator of bone formation. A sclerostin-neutralizing antibody (Scl-Ab) increased bone mineral density in women with postmenopausal osteoporosis and healthy men. The objective of this study is to characterize the condition of bone loss in ovariectomized (OVX) rats with concurrent mechanical unloading and evaluate the effect of sclerostin antibody treatment in mitigating the prospective severe bone loss conditions in this model. Four-month-old OVX- or sham-operated female SD rats were used in this study. They were subjected to functional disuse induced by hind-limb suspension (HLS) or free ambulance after 2 days of arrival. Subcutaneous injections with either vehicle or Scl-Ab at 25mg/kg were made twice per week for 5 weeks from the time of HLS. μCT analyses demonstrated a significant decrease in distal metaphyseal trabecular architecture integrity with HLS, OVX and HLS+OVX (Bone volume fraction decreased by 29%, 71% and 87% respectively). The significant improvement of various trabecular bone parameters (Bone volume fraction increased by 111%, 229% and 297% respectively as compared with placebo group) with the administration of Scl-Ab are associated with stronger mechanical property and increased bone formation by histomorphometry. These results together indicate that Scl-Ab prevented the loss of trabecular bone mass and cortical bone strength in OVX rat model with concurrent mechanical unloading. The data suggested that monoclonal sclerostin-neutralizing antibody represents a promising therapeutic approach for severe osteoporosis induced by estrogen deficiency with concurrent mechanical unloading.