CaSR modulates proliferation of the superficial zone cells in temporomandibular joint cartilage via the PTHrP nuclear localization sequence
CaSR modulates proliferation of the superficial zone cells in temporomandibular joint cartilage via the PTHrP nuclear localization sequence
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DOI：
10.1096/fj.202300037rr
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发表时间：
2023-07
期刊：
影响因子：
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通讯作者：
Peng Zhou;Hongxu Yang;Mian Zhang;Jinqiang Liu;Jia Yu;Shibin Yu;Qian Liu;YUE‐AN Zhang;Mian‐jiao Xie;Xiaojie Xu;Jiguang Liu;Mei‐qing Wang
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作者：
Peng Zhou;Hongxu Yang;Mian Zhang;Jinqiang Liu;Jia Yu;Shibin Yu;Qian Liu;YUE‐AN Zhang;Mian‐jiao Xie;Xiaojie Xu;Jiguang Liu;Mei‐qing Wang
下颌髁突软骨浅表带细胞增生。本研究旨在探讨钙敏感受体（CaSR）与甲状旁腺激素相关肽核定位序列（PTHrP87‐139）的关系及其在浅表带细胞增殖行为中的作用。在体外流体流动剪切应力（FFSS）模型和体内双侧抬高咬合模型中使用了功能增益和功能损失策略，结果显示下颌髁突软骨增厚。CaSR和PTHrP87‐139是通过用激活剂/SiRNA处理分离的浅表带细胞，以及在他莫昔芬诱导模式下，用蛋白多糖4启动子基因（Prg4‐CreERT2）删除CaSR或甲状旁腺激素相关肽（PTHrP）基因，同时或不额外注射CaSR激动剂Cinacalcet或PTHrP87‐139肽。FFSS刺激了CaSR和PTHrP的表达，并加速了表达Prg4的浅表带细胞的增殖，在这一过程中，CaSR起到了PTHrP的上行流的作用。蛋白多糖4特异性敲除CaSR或PTHrP可降低软骨厚度，抑制浅表带细胞增殖和早期分化，抑制双侧抬高咬合促进的软骨增厚和基质生成。注射CaSR激动剂Cinacalcet不能改善PTHrP突变引起的表型。注射PTHrP87‐139肽可使软骨免于CaSR基因的敲除。CaSR通过激活PTHrP核定位序列调控下颌髁突软骨浅带细胞的增殖。我们的数据支持CaSR的治疗靶点，即促进浅带软骨中PTHrP的产生。
The superficial zone cells in mandibular condylar cartilage are proliferative. The present purpose was to delineate the relation of calcium‐sensing receptor (CaSR) and parathyroid hormone‐related peptide nuclear localization sequence (PTHrP87‐139), and their role in the proliferation behaviors of the superficial zone cells. A gain‐ and loss‐of‐function strategy were used in an in vitro fluid flow shear stress (FFSS) model and an in vivo bilateral elevation bite model which showed mandibular condylar cartilage thickening. CaSR and PTHrP87‐139 were modulated through treating the isolated superficial zone cells with activator/SiRNA and via deleting CaSR or parathyroid hormone‐related peptide (PTHrP) gene in mice with the promoter gene of proteoglycan 4 (Prg4‐CreERT2) in the tamoxifen‐inducible pattern with or without additional injection of Cinacalcet, the CaSR agonist, or PTHrP87‐139 peptide. FFSS stimulated CaSR and PTHrP expression, and accelerated proliferation of the Prg4‐expressing superficial zone cells, in which process CaSR acted as an up‐streamer of PTHrP. Proteoglycan 4 specific knockout of CaSR or PTHrP reduced the cartilage thickness, suppressed the proliferation and early differentiation of the superficial zone cells, and inhibited cartilage thickening and matrix production promoted by bilateral elevation bite. Injections of CaSR agonist Cinacalcet could not improve the phenotype caused by PTHrP mutation. Injections of PTHrP87‐139 peptide rescued the cartilage from knockout of CaSR gene. CaSR modulates proliferation of the superficial zone cells in mandibular condylar cartilage through activation of PTHrP nuclear localization sequence. Our data support the therapeutic target of CaSR in promoting PTHrP production in superficial zone cartilage.