SDF-1/CXCR4 axis coordinates crosstalk between subchondral bone and articular cartilage in osteoarthritis pathogenesis
SDF-1/CXCR4 axis coordinates crosstalk between subchondral bone and articular cartilage in osteoarthritis pathogenesis
复制标题
SDF-1/CXCR4轴协调骨关节炎发病机制中软骨下骨和关节软骨之间的串扰
DOI：
10.1016/j.bone.2019.05.010
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发表时间：
2019-08-01
期刊：
影响因子：
4.1
通讯作者：
Cui, Zhuang
中科院分区：
文献类型：
--
作者：
Qin, Han-Jun;Xu, Ting;Cui, Zhuang
软骨下骨和关节软骨之间的相互作用被认为是骨关节炎（OA）发生和发展的中心特征，但其潜在的分子机制仍然是一个谜。同时，药物在软骨下骨的特异性给药也是研究过程中的一大挑战。本研究旨在探讨基质细胞衍生因子1（SDF-1）/C-X-C趋化因子受体4型（CXCR 4）轴在OA发病机制中软骨下骨与关节软骨之间的相互作用中的作用。我们发现，在前交叉韧带横断（ACLT）小鼠中，由于错误的间充质干细胞（MSC）募集和过度的骨吸收，软骨下骨中SDF-1的增加首先诱导软骨下骨恶化。然后，软骨下骨的恶化导致SDF-1从软骨下骨到上覆软骨的横向移动。最后，来自底层软骨下骨的SDF-1与软骨细胞中的CXCR 4结合，通过促进软骨细胞中转化生长因子β受体I型（T β RI）从激活素受体样激酶5（ALKS）转移到激活素受体样激酶1（ALK 1）来诱导关节软骨降解。更重要的是，在ACLT大鼠中特异性抑制SDF-1/CXCR 4轴通过稳定软骨下骨微结构、减少软骨中的SDF-1和消除软骨细胞中T β RI的移位来减轻OA。我们的数据表明，SDF-1/CXCR 4轴可能协调OA发病机制中软骨下骨和关节软骨之间的串扰。因此，特异性抑制软骨下骨中SDF-1/CXCR 4轴或干预SDF-1穿过可能是OA的治疗靶点。
Crosstalk between subchondral bone and articular cartilage is considered a central feature of osteoarthritis (OA) initiation and progression, but its underlying molecular mechanism remains elusive. Meanwhile, specific administration of drugs in subchondral bone is also a great challenge during investigation of the process. We here explore the role of stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4) axis in the crosstalk between subchondral bone and articular cartilage in OA pathogenesis, using osmotic infusion pumps implanted in tibial subchondral bone directly to ensure quantitative, continuous and steady drug delivery over the entire experiment. We found that increased SDF-1 in subchondral bone firstly induced subchondral bone deterioration by erroneous Mesenchymal Stem Cells (MSCs) recruitment and excessive bone resorption in anterior cruciate ligament transection (ACLT) mice. Deterioration of subchondral bone then led to the traverse of SDF-1 from subchondral bone to overlying cartilage. Finally, SDF-1 from underlying subchondral bone combined with CXCR4 in chondrocytes to induce articular cartilage degradation by promoting the shift of transforming growth factor-beta receptor type I (T beta RI) in chondrocytes from activin receptor-like kinase 5 (ALKS) to activin receptor-like kinase 1 (ALK1). More importantly, specific inhibition of SDF-1/CXCR4 axis in ACLT rats attenuated OA by stabilizing subchondral bone microarchitecture, reducing SDF-1 in cartilage and abrogating the shift of T beta RI in chondrocytes. Our data demonstrate that the SDF-1/CXCR4 axis may coordinate the crosstalk between subchondral bone and articular cartilage in OA pathogenesis. Therefore, specific inhibition of SDF-1/CXCR4 axis in subchondral bone or intervention in SDF-1 traverse may be therapeutic targets for OA.