Department of Spine Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Guangdong Province Key Laboratory of Orthopaedics and Traumatology, Guangzhou, China.
EMBO Mol Med. 2020 Dec 7;12(12):e12109. doi: 10.15252/emmm.202012109. Epub 2020 Dec 1.
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.
病理性新骨形成是强直性脊柱炎（AS）的典型病理特征，其潜在的分子机制仍不清楚。先前的研究表明，钙敏感受体（CaSR）对成骨分化至关重要，同时也与许多炎症性疾病密切相关。然而，它是否在 AS 的病理性新骨形成中发挥作用尚未有报道。在这里，我们首次报道了 CaSR 的表达在来自 AS 患者和具有不同潜在发病机制的动物模型的肌腱组织中异常上调的证据。CaSR 的系统抑制减少了动物模型中病理性新骨形成的发生率和强直性表型的严重程度。CaSR 通过 PLCγ 信号通路在体外和体内促进骨形成。此外，各种炎症细胞因子通过 NF-κB/p65 和 JAK/Stat3 通路在上皮细胞中诱导 CaSR 的上调。这些新发现表明，炎症诱导的 CaSR 异常上调和上皮细胞中 CaSR-PLCγ 信号通路的激活作为炎症的介质，影响 AS 中的病理性新骨形成。
