The proton-activated G protein-coupled receptor GPR4 regulates the development of osteoarthritis via modulating CXCL12/CXCR7 signaling.
The proton-activated G protein-coupled receptor GPR4 regulates the development of osteoarthritis via modulating CXCL12/CXCR7 signaling.
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质子激活 G 蛋白偶联受体 GPR4 通过调节 CXCL12/CXCR7 信号传导调节骨关节炎的发展
DOI：
10.1038/s41419-021-04455-4
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发表时间：
2022-02-14
影响因子：
9
通讯作者：
Luo J
中科院分区：
文献类型：
--
作者：
Li R;Guan Z;Bi S;Wang F;He L;Niu X;You Y;Liu Y;Ding Y;Siwko S;Wang N;Zhang Z;Jin Y;Luo J
炎症性疾病会降低细胞外环境 pH 值。然而，质子激活G蛋白偶联受体（GPCR）是否可以调节骨关节炎（OA）的发展尚不清楚。在这项研究中，我们报告质子激活的 GPR4 对于 OA 的发展至关重要。我们发现人和小鼠 OA 软骨中质子激活的 GPR4 表达显着增加。慢病毒介导的GPR4在小鼠关节中的过度表达加速了OA的发展，包括促进关节软骨损伤、滑膜增生和骨赘形成，而Gpr4敲除有效地减弱了小鼠创伤后和衰老相关的OA的发展。我们还发现，用拮抗剂 NE52-QQ57 抑制 GPR4 可改善小鼠的 OA 进展，促进细胞外基质 (ECM) 的产生，并保护人类关节软骨外植体中的软骨免于降解。此外，在促炎和微酸性条件下，GPR4过表达会上调基质降解酶的表达和炎症因子。从机制上讲，GPR4 通过调节 CXCR7/CXCL12 的表达，通过 NF-κB/MAPK 信号激活来抑制软骨细胞分化并上调软骨稳态。总之，我们的结果率先说明质子激活的 GPCR 作为体内 OA 发病机制的关键调节因子，并支持 GPR4 可能成为 OA 治疗的一个有前途的治疗靶点。
Inflammatory diseases decrease the extracellular environmental pH. However, whether proton-activated G protein-coupled receptors (GPCRs) can regulate the development of osteoarthritis (OA) is largely unknown. In this study, we report that proton-activated GPR4 is essential for OA development. We found a marked increase in expression of the proton-activated GPR4 in human and mouse OA cartilage. Lentivirus-mediated overexpression of GPR4 in mouse joints accelerated the development of OA, including promotion of articular cartilage damage, synovial hyperplasia, and osteophyte formation, while Gpr4 knockout effectively attenuated the development of posttraumatic and aging-associated OA in mice. We also found that inhibition of GPR4 with the antagonist NE52-QQ57 ameliorated OA progression in mice, promoted extracellular matrix (ECM) production, and protected cartilage from degradation in human articular cartilage explants. Moreover, GPR4 overexpression upregulated matrix-degrading enzymes’ expression and inflammation factors under pro-inflammatory and slightly acidic conditions. Mechanistically, GPR4 suppressed chondrocyte differentiation and upregulated cartilage homeostasis through NF-κB/MAPK signaling activation by regulating CXCR7/CXCL12 expression. Together, our results take the lead to illustrate that proton-activated GPCR acts as a key regulator for OA pathogenesis in vivo, and support that GPR4 could be a promising therapeutic target for OA treatment.
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作者：
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