Aberrant upregulation of CaSR promotes pathological new bone formation in ankylosing spondylitis.
Aberrant upregulation of CaSR promotes pathological new bone formation in ankylosing spondylitis.
复制标题
CaSR 的异常上调促进强直性脊柱炎病理性新骨形成
DOI：
10.15252/emmm.202012109
复制
发表时间：
2020-12-07
影响因子：
11.1
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Li X;Chen S;Hu Z;Chen D;Wang J;Li Z;Li Z;Cui H;Dai G;Liu L;Wang H;Zhang K;Zheng Z;Zhan Z;Liu H
病理性新骨形成是强直性脊柱炎（AS）的典型病理特征，其分子机制尚不清楚。先前的研究表明，钙敏感受体（CaSR）对于成骨分化至关重要，同时也高度参与许多炎症性疾病。然而，它是否在AS的病理性新骨形成中起作用尚未见报道。在这里，我们报告的第一个证据表明，表达的CaSR是异常上调的附着点组织收集的AS患者和动物模型与不同的假设类型的发病机制。在动物模型中，全身性抑制CaSR可降低病理性新骨形成的发生率和强直性表型的严重程度。CaSR激活PLC γ信号通路促进体内外骨形成。此外，各种炎性细胞因子通过NF-κ B/p65和JAK/Stat3途径诱导成骨细胞中CaSR的上调。这些新的发现表明，炎症诱导的成骨细胞中CaSR的异常上调和CaSR-PLC γ信号转导的激活作为炎症介质，影响AS中的病理性新骨形成。本研究确定了炎症诱导的CaSR异常上调在强直性脊柱炎（AS）病理性新骨形成过程中的关键作用。靶向CaSR可能是一种新的潜在的治疗策略，以减缓轴结构强直的进展。
Pathological new bone formation is a typical pathological feature in ankylosing spondylitis (AS), and the underlying molecular mechanism remains elusive. Previous studies have shown that the calcium‐sensing receptor (CaSR) is critical for osteogenic differentiation while also being highly involved in many inflammatory diseases. However, whether it plays a role in pathological new bone formation of AS has not been reported. Here, we report the first piece of evidence that expression of CaSR is aberrantly upregulated in entheseal tissues collected from AS patients and animal models with different hypothetical types of pathogenesis. Systemic inhibition of CaSR reduced the incidence of pathological new bone formation and the severity of the ankylosing phenotype in animal models. Activation of PLCγ signalling by CaSR promoted bone formation both in vitro and in vivo. In addition, various inflammatory cytokines induced upregulation of CaSR through NF‐κB/p65 and JAK/Stat3 pathways in osteoblasts. These novel findings suggest that inflammation‐induced aberrant upregulation of CaSR and activation of CaSR‐PLCγ signalling in osteoblasts act as mediators of inflammation, affecting pathological new bone formation in AS. This study identifies a critical role of inflammation‐induced aberrant upregulation of CaSR in the process of pathological new bone formation in ankylosing spondylitis (AS). Targeting CaSR may be a novel potential therapeutic strategy to slow down the progression of axial structural ankylosis.
登录
查看更多内容
影响因子：
7.3
作者：
Chang W;Tu C;Chen TH;Bikle D;Shoback D
通讯作者：
Shoback D
DOI：
10.1002/jbmr.3864
发表时间：
2020-01
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Cheng Z;Li A;Tu CL;Maria CS;Szeto N;Herberger A;Chen TH;Song F;Wang J;Liu X;Shoback DM;Chang W
通讯作者：
Chang W
影响因子：
--
作者：
Berlo, Suzanne E.;Guichelaar, Teun;Glant, Tibor T.
通讯作者：
Glant, Tibor T.
影响因子：
27.4
作者：
Jacques, Peggy;Lambrecht, Stijn;Elewaut, Dirk
通讯作者：
Elewaut, Dirk
影响因子：
--
作者：
Hanyecz, A;Berlo, SE;Glant, TT
通讯作者：
Glant, TT