Modulating hedgehog signaling can attenuate the severity of osteoarthritis
Modulating hedgehog signaling can attenuate the severity of osteoarthritis
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DOI：
10.1038/nm.2055
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发表时间：
2009-12-01
期刊：
影响因子：
82.9
通讯作者：
Alman, Benjamin A.
中科院分区：
文献类型：
--
作者：
Lin, Alvin C.;Seeto, Brian L.;Alman, Benjamin A.
骨性关节炎与关节软骨不可逆转的退变有关。值得注意的是，在这种情况下，关节软骨软骨细胞经历了表型和基因表达的变化，这使人想起它们在骨骼发育过程中生长板中的终末分化(1，2)。Hhedgehog(HH)信号调节正常软骨细胞的生长和分化(3-8)；然而，HH信号在骨关节炎软骨细胞中的作用尚不清楚。在这里，我们研究了人类骨关节炎样本和手术诱导骨关节炎的小鼠，发现HH信号在骨关节炎中被激活。利用几只转基因小鼠，我们发现软骨细胞中HH信号水平较高会导致更严重的骨关节炎表型。此外，我们在小鼠和人类软骨外植体中表明，药物或遗传抑制HH信号可以降低骨关节炎的严重程度，并且矮小相关转录因子-2(RUNX2)可能通过调节具有血栓反应蛋白类型1基序的去整合素和金属蛋白酶(ADAMTS5)的表达来调节这一过程。总之，这些发现增加了HH阻滞剂可以作为一种治疗方法来抑制关节软骨退变的可能性。
Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development(1,2). Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation(3-8); however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here we examine human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, we found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, we show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runt-related transcription factor-2 (RUNX2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.