Echtermeyer Frank, Bertrand Jessica, Dreier Rita, Meinecke Ingmar, Neugebauer Katja, Fuerst Martin, Lee Yun Jong, Song Yeong Wook, Herzog Christine, Theilmeier Gregor, Pap Thomas
Department of Anesthesiology and Intensive Care Medicine, Medical University Hannover, Hannover, Germany.
Nat Med. 2009 Sep;15(9):1072-6. doi: 10.1038/nm.1998. Epub 2009 Aug 16.
Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen-producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4-specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage destruction in both syndecan-4-deficient mice and syndecan-4-specific antibody-treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.
具有血小板反应蛋白基序的解聚素和金属蛋白酶5（ADAMTS-5）对软骨蛋白聚糖的切割在骨关节炎（一种导致关节结构进行性破坏的退行性关节疾病）过程中软骨基质的降解至关重要。ADAMTS-5激活的机制及其与骨关节炎发病机制的联系仍知之甚少，但已表明多配体蛋白聚糖参与了ADAMTS-4的激活（参考文献3）。在此我们表明，在人类骨关节炎以及该疾病的小鼠模型中，多配体蛋白聚糖-4在产生X型胶原蛋白的软骨细胞中特异性诱导表达。在基因改造小鼠中多配体蛋白聚糖-4的缺失以及向野生型小鼠关节内注射多配体蛋白聚糖-4特异性抗体，可防止蛋白聚糖丢失，从而在手术诱导的骨关节炎模型中预防骨关节炎性软骨损伤。在多配体蛋白聚糖-4缺陷小鼠和多配体蛋白聚糖-4特异性抗体处理的野生型小鼠中，骨关节炎样软骨破坏较轻的情况是由于ADAMTS-5活性显著降低所致。多配体蛋白聚糖-4通过与该蛋白酶直接相互作用以及通过调节丝裂原活化蛋白激酶（MAPK）依赖的基质金属蛋白酶-3（MMP-3）合成来控制ADAMTS-5的激活。我们的数据表明，旨在抑制多配体蛋白聚糖-4的策略对于治疗骨关节炎中的软骨损伤具有重要价值。
