Increased Osteoblastic Cxcl9 Contributes to the Uncoupled Bone Formation and Resorption in Postmenopausal Osteoporosis
Increased Osteoblastic Cxcl9 Contributes to the Uncoupled Bone Formation and Resorption in Postmenopausal Osteoporosis
复制标题
成骨细胞 Cxcl9 增加有助于绝经后骨质疏松症中不耦合的骨形成和吸收
DOI：
10.2147/cia.s254885
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发表时间：
2020-01-01
影响因子：
3.6
通讯作者：
Li, Qingchu
中科院分区：
文献类型：
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作者：
Liu, Zezheng;Liang, Wenquan;Li, Qingchu
雌激素缺乏导致绝经后骨质疏松症的骨质流失，因为骨形成虽然增强，但不能跟上受刺激的破骨细胞骨吸收的步伐。驱动这种解偶联的机制是绝经后骨质疏松症发病机制的核心，然而，这一点仍然知之甚少。我们之前发现成骨细胞分泌的Cxcl9抑制骨生成，而Cxcl9在破骨细胞骨吸收和骨质疏松中的作用尚不清楚。材料与方法采用双侧卵巢切除术（OVX）建立绝经后骨质疏松小鼠模型。原位杂交检测骨组织中Cxcl9 mRNA的表达。ELISA法测定骨和血清中Cxcl9的浓度。Cxcl9的活性被中和抗体阻断。采用Micro-CT检测Cxcl9中和对骨结构的影响。通过细胞迁移和粘附实验评价Cxcl9对破骨细胞活性的影响。采用TRAP染色和Western blot检测破骨细胞分化情况。将CXCR3拮抗剂NBI-74,330或ERK拮抗剂SCH772984用于破骨细胞，研究Cxcl9对CXCR3/ERK信号传导的影响。结果Cxcl9在OVX小鼠骨中表达和分泌增多。中和骨髓中的Cxcl9通过促进骨形成和抑制骨吸收来防止小鼠骨丢失。体外，成骨细胞分泌的Cxcl9促进破骨细胞前体粘附、迁移并向成熟破骨细胞分化。成骨细胞Cxcl9对破骨细胞的积极作用通过阻断破骨细胞中的CXCR3/ERK信号通路而被消除。雌激素负向调节成骨细胞中Cxcl9的表达和分泌，解释了OVX小鼠骨中Cxcl9浓度升高的原因。结论本研究阐明了Cxcl9在骨质疏松骨中抑制骨形成和促进骨吸收的作用，为绝经后骨质疏松症的治疗提供了可能的治疗靶点。
Introduction Estrogen deficiency leads to bone loss in postmenopausal osteoporosis, because bone formation, albeit enhanced, fails to keep pace with the stimulated osteoclastic bone resorption. The mechanism driving this uncoupling is central to the pathogenesis of postmenopausal osteoporosis, which, however, remains poorly understood. We previously found that Cxcl9 secreted by osteoblasts inhibited osteogenesis in bone, while the roles of Cxcl9 on osteoclastic bone resorption and osteoporosis are unclear. Materials and Methods Postmenopausal osteoporosis mouse model was established by bilateral surgical ovariectomy (OVX). In situ hybridization was performed to detect Cxcl9 mRNA expression in bone. ELISA assay was conducted to assess Cxcl9 concentrations in bone and serum. Cxcl9 activity was blocked by its neutralizing antibody. Micro-CT was performed to determine the effects of Cxcl9 neutralization on bone structure. Cell Migration and adhesion assay were conducted to evaluate the effects of Cxcl9 on osteoclast activity. TRAP staining and Western blot were performed to assess osteoclast differentiation. CXCR3 antagonist NBI-74,330 or ERK antagonist SCH772984 was administered to osteoclast to study the effects of Cxcl9 on CXCR3/ERK signaling. Results Cxcl9 was expressed and secreted increasingly in OVX mice bone. Neutralizing Cxcl9 in bone marrow prevented bone loss in the mice by facilitating bone formation as well as inhibiting bone resorption. In vitro, Cxcl9 secreted from osteoblasts facilitated osteoclast precursors adhesion, migration and their differentiation into mature osteoclasts. The positive role of osteoblastic Cxcl9 on osteoclasts was eliminated by blocking CXCR3/ERK signaling in osteoclasts. Estrogen negatively regulated Cxcl9 expression and secretion in osteoblasts, explaining the increased Cxcl9 concentration in OVX mice bone. Conclusion Our study illustrates the roles of Cxcl9 in inhibiting bone formation and stimulating bone resorption in osteoporotic bone, therefore providing a possible therapeutic target to the treatment of postmenopausal osteoporosis.