Membrane-type I metalloproteinase (MT1-MMP/MMP14) plays a key role in various pathophysiological processes, indicating an unaddressed need for a targeted therapeutic approach. However, mice genetically deficient in Mmp14 show severe defects in development and growth. To investigate the possibility of MT1-MMP inhibition as a safe treatment in adults, we generated global Mmp14 tamoxifen-induced conditional knockout (Mmp14^kd) mice and found that MT1-MMP deficiency in adult mice resulted in severe inflammatory arthritis. Mmp14^kd mice started to show noticeably swollen joints two weeks after tamoxifen administration, which progressed rapidly. Mmp14^kd mice reached a humane endpoint 6 to 8 weeks after tamoxifen administration due to severe arthritis. Plasma TNF-α levels were also significantly increased in Mmp14^kd mice. Detailed analysis revealed chondrocyte hypertrophy, synovial fibrosis, and subchondral bone remodeling in the joints of Mmp14^kd mice. However, global conditional knockout of MT1-MMP in adult mice did not affect body weight, blood glucose, or plasma cholesterol and triglyceride levels. Furthermore, we observed substantial expression of MT1-MMP in the articular cartilage of patients with osteoarthritis. We then developed chondrocyte-specific Mmp14 tamoxifen-induced conditional knockout (Mmp14^chkd) mice. Chondrocyte MT1-MMP deficiency in adult mice also caused apparent chondrocyte hypertrophy. However, Mmp14^chkd mice did not exhibit synovial hyperplasia or noticeable arthritis, suggesting that chondrocyte MT1-MMP is not solely responsible for the onset of severe arthritis observed in Mmp14^kd mice. Our findings also suggest that highly cell-type specific inhibition of MT1-MMP is required for its potential therapeutic use.

I 型膜金属蛋白酶 (MT1-MMP/MMP14) 在各种病理生理过程中发挥着关键作用，表明对靶向治疗方法的需求尚未得到解决。然而，Mmp14基因缺陷的小鼠在发育和生长方面表现出严重缺陷。为了研究 MT1-MMP 抑制作为成人安全治疗的可能性，我们培育了全Mmp14他莫昔芬诱导的条件性敲除 ( Mmp14 ^kd ) 小鼠，发现成年小鼠 MT1-MMP 缺乏会导致严重的炎症性关节炎。Mmp14 ^kd小鼠在给予他莫昔芬两周后开始表现出明显的关节肿胀，并且进展迅速。由于严重关节炎，Mmp14 ^{kd小鼠在给予他莫昔芬 6 至 8 周后达到人道终点。}Mmp14 ^kd小鼠的血浆 TNF-α 水平也显着增加。详细分析揭示了Mmp14 ^kd小鼠关节中的软骨细胞肥大、滑膜纤维化和软骨下骨重塑。然而，在成年小鼠中全面条件性敲除 MT1-MMP 并不影响体重、血糖或血浆胆固醇和甘油三酯水平。此外，我们观察到骨关节炎患者的关节软骨中有大量 MT1-MMP 表达。然后，我们开发了软骨细胞特异性Mmp14他莫昔芬诱导的条件敲除 ( Mmp14 ^chkd ) 小鼠。成年小鼠软骨细胞 MT1-MMP 缺乏也会导致明显的软骨细胞肥大。然而，Mmp14 ^chkd小鼠没有表现出滑膜增生或明显的关节炎，这表明软骨细胞 MT1-MMP 并不是 Mm ​​p14 ^kd小鼠中观察到的严重关节炎发作的唯一原因。我们的研究结果还表明，MT1-MMP 的潜在治疗用途需要高度细胞类型特异性抑制。