Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis.
Matrix-Bound Growth Factors are Released upon Cartilage Compression by an Aggrecan-Dependent Sodium Flux that is Lost in Osteoarthritis.
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DOI：
10.1093/function/zqab037
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Vincent TL
中科院分区：
文献类型：
--
作者：
Keppie SJ;Mansfield JC;Tang X;Philp CJ;Graham HK;Önnerfjord P;Wall A;McLean C;Winlove CP;Sherratt MJ;Pavlovskaya GE;Vincent TL
关节软骨是一种致密的细胞外基质丰富的组织，在慢性机械应力后降解，导致骨关节炎（OA）。该组织具有低内在修复，特别是在老年和骨关节炎关节中。在这里，我们描述了三种促再生因子：成纤维细胞生长因子2（FGF 2）、结缔组织生长因子、转化生长因子-β（CTGF-TGFβ）和肝癌衍生生长因子（HDGF），它们在机械损伤时从关节软骨的细胞周基质（PCM）中快速释放。所有三种生长因子结合硫酸乙酰肝素，并被外源性NaCl取代。我们假设，钠，螯合在聚集蛋白聚糖丰富的基质，释放有害的压缩，从而提高细胞周围生长因子的生物利用度。事实上，当软骨聚集蛋白聚糖被IL-1处理耗尽时，生长因子释放被废除，并且在严重受损的人骨关节炎软骨中。通过23 Na-MRI在关节面正下方观察到机械压迫软骨后游离基质钠的流动。这对应于通过扫描声学显微镜和二次谐波发生显微镜测量的组织硬度降低的区域，并且其中Smad 2/3在循环压缩时被磷酸化。我们的研究结果描述了一种新的内在修复机制，由基质刚度控制和介导的游离钠浓度，其中硫酸乙酰肝素结合的生长因子在损伤负荷后从软骨中释放。他们将聚集蛋白聚糖确定为螯合钠的仓库，解释了为什么骨关节炎组织失去了修复能力。预计恢复基质钠以允许在负荷时适当释放生长因子的治疗能够实现OA中的内在软骨修复。骨关节炎是最普遍的肌肉骨骼疾病，影响全球2.5亿人。我们确定了一种新的内在修复反应软骨，介导的聚集蛋白聚糖依赖性钠流量，并依赖于基质硬度，这导致在损伤后释放的鸡尾酒促再生生长因子。晚期骨关节炎中聚集蛋白聚糖的丢失阻止了生长因子的释放，并可能导致疾病进展。在骨关节炎中恢复基质钠的治疗可以恢复内在修复反应以改善疾病结局。随着时间推移的新分数的评估揭示了对肌肉胶原蛋白中蛋白质稳定性维持的洞察。
Articular cartilage is a dense extracellular matrix-rich tissue that degrades following chronic mechanical stress, resulting in osteoarthritis (OA). The tissue has low intrinsic repair especially in aged and osteoarthritic joints. Here, we describe three pro-regenerative factors; fibroblast growth factor 2 (FGF2), connective tissue growth factor, bound to transforming growth factor-beta (CTGF-TGFβ), and hepatoma-derived growth factor (HDGF), that are rapidly released from the pericellular matrix (PCM) of articular cartilage upon mechanical injury. All three growth factors bound heparan sulfate, and were displaced by exogenous NaCl. We hypothesised that sodium, sequestered within the aggrecan-rich matrix, was freed by injurious compression, thereby enhancing the bioavailability of pericellular growth factors. Indeed, growth factor release was abrogated when cartilage aggrecan was depleted by IL-1 treatment, and in severely damaged human osteoarthritic cartilage. A flux in free matrix sodium upon mechanical compression of cartilage was visualised by 23Na -MRI just below the articular surface. This corresponded to a region of reduced tissue stiffness, measured by scanning acoustic microscopy and second harmonic generation microscopy, and where Smad2/3 was phosphorylated upon cyclic compression. Our results describe a novel intrinsic repair mechanism, controlled by matrix stiffness and mediated by the free sodium concentration, in which heparan sulfate-bound growth factors are released from cartilage upon injurious load. They identify aggrecan as a depot for sequestered sodium, explaining why osteoarthritic tissue loses its ability to repair. Treatments that restore matrix sodium to allow appropriate release of growth factors upon load are predicted to enable intrinsic cartilage repair in OA. Osteoarthritis is the most prevalent musculoskeletal disease, affecting 250 million people worldwide. We identify a novel intrinsic repair response in cartilage, mediated by aggrecan-dependent sodium flux, and dependent upon matrix stiffness, which results in the release of a cocktail of pro-regenerative growth factors after injury. Loss of aggrecan in late-stage osteoarthritis prevents growth factor release and likely contributes to disease progression. Treatments that restore matrix sodium in osteoarthritis may recover the intrinsic repair response to improve disease outcome. Assessment of fraction new over time reveals insight into proteostatic maintenance in muscle collagen.
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