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Decorin regulates cartilage pericellular matrix micromechanobiology
Matrix Biology ( IF 4.5 ) Pub Date : 2020-11-25 , DOI: 10.1016/j.matbio.2020.11.002
Daphney R Chery 1 , Biao Han 1 , Ying Zhou 2 , Chao Wang 1 , Sheila M Adams 3 , Prashant Chandrasekaran 1 , Bryan Kwok 1 , Su-Jin Heo 4 , Motomi Enomoto-Iwamoto 5 , X Lucas Lu 6 , Dehan Kong 2 , Renato V Iozzo 7 , David E Birk 3 , Robert L Mauck 4 , Lin Han 1
Affiliation  

In cartilage tissue engineering, one key challenge is for regenerative tissue to recapitulate the biomechanical functions of native cartilage while maintaining normal mechanosensitive activities of chondrocytes. Thus, it is imperative to discern the micromechanobiological functions of the pericellular matrix, the ~ 2–4 µm-thick domain that is in immediate contact with chondrocytes. In this study, we discovered that decorin, a small leucine-rich proteoglycan, is a key determinant of cartilage pericellular matrix micromechanics and chondrocyte mechanotransduction in vivo. The pericellular matrix of decorin-null murine cartilage developed reduced content of aggrecan, the major chondroitin sulfate proteoglycan of cartilage and a mild increase in collagen II fibril diameter vis-à-vis wild-type controls. As a result, decorin-null pericellular matrix showed a significant reduction in micromodulus, which became progressively more pronounced with maturation. In alignment with the defects of pericellular matrix, decorin-null chondrocytes exhibited decreased intracellular calcium activities, [Ca2+]i, in both physiologic and osmotically evoked fluidic environments in situ, illustrating impaired chondrocyte mechanotransduction. Next, we compared [Ca2+]i activities of wild-type and decorin-null chondrocytes following enzymatic removal of chondroitin sulfate glycosaminoglycans. The results showed that decorin mediates chondrocyte mechanotransduction primarily through regulating the integrity of aggrecan network, and thus, aggrecan-endowed negative charge microenvironment in the pericellular matrix. Collectively, our results provide robust genetic and biomechanical evidence that decorin is an essential constituent of the native cartilage matrix, and suggest that modulating decorin activities could improve cartilage regeneration.



中文翻译:

核心蛋白聚糖调节软骨细胞周围基质微机械生物学

在软骨组织工程中,一个关键挑战是再生组织在维持软骨细胞的正常机械敏感性活动的同时重现天然软骨的生物力学功能。因此,必须辨别细胞周围基质的微机械生物学功能,即与软骨细胞直接接触的约 2-4 µm 厚的区域。在这项研究中,我们发现核心蛋白聚糖是一种富含亮氨酸的小蛋白聚糖,是体内软骨细胞周围基质微力学和软骨细胞机械转导的关键决定因素。核心蛋白聚糖缺失小鼠软骨的细胞外基质减少了蛋白聚糖、软骨的主要硫酸软骨素蛋白多糖和胶原蛋白 II 原纤维直径相对于野生型对照。结果,无核心蛋白聚糖的细胞周基质显示出显着降低的微模量,随着成熟逐渐变得更加明显。与细胞周围基质的缺陷相一致,核心蛋白缺失软骨细胞在生理和渗透诱发的原位流体环境中表现出细胞内钙活性降低,[Ca 2+ ] i,说明软骨细胞机械传导受损。接下来,我们比较了 [Ca 2+ ] i酶去除硫酸软骨素糖胺聚糖后野生型和核心蛋白聚糖缺失软骨细胞的活性。结果表明,核心蛋白聚糖主要通过调节蛋白聚糖网络的完整性来介导软骨细胞的机械转导,从而调节细胞外基质中蛋白聚糖赋予的负电荷微环境。总的来说,我们的结果提供了强有力的遗传和生物力学证据,证明核心蛋白聚糖是天然软骨基质的重要组成部分,并表明调节核心蛋白聚糖活性可以改善软骨再生。

更新日期:2020-11-25
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