Bai Xiao-Hui, Wang Da-Wei, Kong Li, Zhang Yan, Luan Yi, Kobayashi Tatsuya, Kronenberg Henry M, Yu Xiu-Ping, Liu Chuan-Ju
Department of Orthopaedic Surgery, New York University School of Medicine, New York, NY 100031, USA.
Mol Cell Biol. 2009 Aug;29(15):4201-19. doi: 10.1128/MCB.00056-09. Epub 2009 Jun 1.
ADAMTS-7, a metalloproteinase that belongs to ADAMTS family, is important for the degradation of cartilage extracellular matrix proteins in arthritis. Herein we report that ADAMTS-7 is upregulated during chondrocyte differentiation and demonstrates the temporal and spatial expression pattern during skeletal development. ADAMTS-7 potently inhibits chondrocyte differentiation and endochondral bone formation, and this inhibition depends on its proteolytic activity. The cysteine-rich domain of ADAMTS-7 is required for its interaction with the extracellular matrix, and the C-terminal four-thrombospondin motifs are necessary for its full proteolytic activity and inhibition of chondrocyte differentiation. ADAMTS-7 is an important target of canonical PTHrP signaling, since (i) PTHrP induces ADAMTS-7, (ii) ADAMTS-7 is downregulated in PTHrP null mutant (PTHrP-/-) growth plate chondrocytes, and (iii) blockage of ADAMTS-7 almost abolishes PTHrP-mediated inhibition of chondrocyte hypertrophy and endochondral bone growth. ADAMTS-7 associates with granulin-epithelin precursor (GEP), an autocrine growth factor that has been implicated in tissue regeneration, tumorigenesis, and inflammation. In addition, ADAMTS-7 acts as a new GEP convertase and neutralizes GEP-stimulated endochondral bone formation. Collectively, these findings demonstrate that ADAMTS-7, a direct target of PTHrP signaling, negatively regulates endochondral bone formation by associating with and inactivating GEP chondrogenic growth factor.
ADAMTS-7是一种属于ADAMTS家族的金属蛋白酶，在关节炎中对软骨细胞外基质蛋白的降解起重要作用。在此我们报告，ADAMTS-7在软骨细胞分化过程中上调，并在骨骼发育过程中呈现出时空表达模式。ADAMTS-7强烈抑制软骨细胞分化和软骨内骨形成，且这种抑制作用取决于其蛋白水解活性。ADAMTS-7富含半胱氨酸的结构域是其与细胞外基质相互作用所必需的，而C末端的四个血小板反应蛋白基序是其完全蛋白水解活性和抑制软骨细胞分化所必需的。ADAMTS-7是经典甲状旁腺激素相关蛋白（PTHrP）信号通路的一个重要靶点，因为：（i）PTHrP诱导ADAMTS-7；（ii）在PTHrP基因敲除（PTHrP-/-）生长板软骨细胞中ADAMTS-7表达下调；（iii）阻断ADAMTS-7几乎消除了PTHrP介导的对软骨细胞肥大和软骨内骨生长的抑制作用。ADAMTS-7与颗粒蛋白-上皮素前体（GEP）相关联，GEP是一种自分泌生长因子，与组织再生、肿瘤发生和炎症有关。此外，ADAMTS-7作为一种新的GEP转化酶，可中和GEP刺激的软骨内骨形成。总的来说，这些发现表明，作为PTHrP信号通路的直接靶点，ADAMTS-7通过与GEP软骨生成生长因子结合并使其失活，从而对软骨内骨形成起负向调节作用。
