Lubricin Contributes to Homeostasis of Articular Cartilage by Modulating Differentiation of Superficial Zone Cells
Lubricin Contributes to Homeostasis of Articular Cartilage by Modulating Differentiation of Superficial Zone Cells
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DOI：
10.1002/jbmr.4226
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发表时间：
2020-12-21
影响因子：
6.2
通讯作者：
Saito, Taku
中科院分区：
文献类型：
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作者：
Maenohara, Yuji;Chijimatsu, Ryota;Saito, Taku
由蛋白聚糖4（Prg 4）基因编码的润滑素由关节软骨和滑膜细胞的浅表区（SFZ）细胞产生，其对于关节表面的润滑是不可缺少的。人类和小鼠Prg 4功能丧失导致早发性关节病，伴有SFZ细胞丢失和滑膜增生。在这里，我们专注于Prg 4基因敲除关节中关节软骨厚度的增加，并分析了潜在的机制。在关节软骨发育的后期，Prg 4基因敲除小鼠关节软骨在2 - 4周增厚，SFZ在8周消失。在培养的Prg 4敲除股骨头中观察到类似的变化。细胞追踪显示，1周龄的Prg 4敲除SFZ细胞在1周后扩展到深层。在体外实验中，Prg 4缺乏粘蛋白样结构域的过度表达显着抑制ATDC 5细胞的分化，而Prg 4敲除SFZ细胞的颗粒显示出增强的分化。RNA测序鉴定基质金属蛋白酶9（Mmp 9）为Prg 4敲除后上调最多的基因。在Prg 4敲除小鼠中，SFZ中表达的Mmp 9被进一步诱导。通过I κ B激酶（IKK）抑制剂处理，Prg 4敲除引起的Mmp 9表达增加被抵消。在Prg 4敲除的细胞团中，Smad 2的磷酸化也得到增强，这被IKK抑制剂所取消。在Prg 4基因敲除的关节中，关节软骨发育过程中Mmp 9和磷酸化Smad 2的表达增强。润滑素通过抑制SFZ细胞的分化而有助于关节软骨的稳态，并且核因子-κ B-Mmp 9-TGF-β途径可能负责润滑素的下游作用。(c)2020年美国骨骼与矿物研究学会（ASBMR）。
Lubricin encoded by the proteoglycan 4 (Prg4) gene is produced from superficial zone (SFZ) cells of articular cartilage and synoviocytes, which is indispensable for lubrication of joint surfaces. Loss-of-function of human and mouse Prg4 results in early-onset arthropathy accompanied by lost SFZ cells and hyperplastic synovium. Here, we focused on increases in the thickness of articular cartilage in Prg4-knockout joints and analyzed the underlying mechanisms. In the late stage of articular cartilage development, the articular cartilage was thickened at 2 to 4 weeks and the SFZ disappeared at 8 weeks in Prg4-knockout mice. Similar changes were observed in cultured Prg4-knockout femoral heads. Cell tracking showed that Prg4-knockout SFZ cells at 1 week of age expanded to deep layers after 1 week. In in vitro experiments, overexpression of Prg4 lacking a mucin-like domain suppressed differentiation of ATDC5 cells markedly, whereas pellets of Prg4-knockout SFZ cells showed enhanced differentiation. RNA sequencing identified matrix metalloproteinase 9 (Mmp9) as the top upregulated gene by Prg4 knockout. Mmp9 expressed in the SFZ was further induced in Prg4-knockout mice. The increased expression of Mmp9 by Prg4 knockout was canceled by I kappa B kinase (IKK) inhibitor treatment. Phosphorylation of Smad2 was also enhanced in Prg4-knockout cell pellets, which was canceled by the IKK inhibitor. Expression of Mmp9 and phosphorylated Smad2 during articular cartilage development was enhanced in Prg4-knockout joints. Lubricin contributes to homeostasis of articular cartilage by suppressing differentiation of SFZ cells, and the nuclear factor-kappa B-Mmp9-TGF-beta pathway is probably responsible for the downstream action of lubricin. (c) 2020 American Society for Bone and Mineral Research (ASBMR).