Little C B, Barai A, Burkhardt D, Smith S M, Fosang A J, Werb Z, Shah M, Thompson E W
Raymond Purves Research Laboratories, University of Sydney at Royal North Shore Hospital, St. Leonard's, New South Wales, Australia.
Arthritis Rheum. 2009 Dec;60(12):3723-33. doi: 10.1002/art.25002.
To investigate the role of matrix metalloproteinase 13 (MMP-13; collagenase 3) in osteoarthritis (OA).
OA was surgically induced in the knees of MMP-13-knockout mice and wild-type mice, and mice were compared. Histologic scoring of femoral and tibial cartilage aggrecan loss (0-3 scale), erosion (0-7 scale), and chondrocyte hypertrophy (0-1 scale), as well as osteophyte size (0-3 scale) and maturity (0-3 scale) was performed. Serial sections were stained for type X collagen and the MMP-generated aggrecan neoepitope DIPEN.
Following surgery, aggrecan loss and cartilage erosion were more severe in the tibia than femur (P<0.01) and tibial cartilage erosion increased with time (P<0.05) in wild-type mice. Cartilaginous osteophytes were present at 4 weeks and underwent ossification, with size and maturity increasing by 8 weeks (P<0.01). There was no difference between genotypes in aggrecan loss or cartilage erosion at 4 weeks. There was less tibial cartilage erosion in knockout mice than in wild-type mice at 8 weeks (P<0.02). Cartilaginous osteophytes were larger in knockout mice at 4 weeks (P<0.01), but by 8 weeks osteophyte maturity and size were no different from those in wild-type mice. Articular chondrocyte hypertrophy with positive type X collagen and DIPEN staining occurred in both wild-type and knockout mouse joints.
Our findings indicate that structural cartilage damage in a mouse model of OA is dependent on MMP-13 activity. Chondrocyte hypertrophy is not regulated by MMP-13 activity in this model and does not in itself lead to cartilage erosion. MMP-13 deficiency can inhibit cartilage erosion in the presence of aggrecan depletion, supporting the potential for therapeutic intervention in established OA with MMP-13 inhibitors.
研究基质金属蛋白酶13（MMP - 13；胶原酶3）在骨关节炎（OA）中的作用。
通过手术在MMP - 13基因敲除小鼠和野生型小鼠的膝关节诱导骨关节炎，然后对小鼠进行比较。对股骨和胫骨软骨蛋白聚糖丢失（0 - 3级）、侵蚀（0 - 7级）、软骨细胞肥大（0 - 1级）以及骨赘大小（0 - 3级）和成熟度（0 - 3级）进行组织学评分。连续切片用X型胶原和MMP产生的蛋白聚糖新表位DIPEN染色。
手术后，野生型小鼠胫骨中的蛋白聚糖丢失和软骨侵蚀比股骨更严重（P<0.01），且胫骨软骨侵蚀随时间增加（P<0.05）。软骨性骨赘在4周时出现并发生骨化，到8周时大小和成熟度增加（P<0.01）。4周时，各基因型在蛋白聚糖丢失或软骨侵蚀方面无差异。8周时，基因敲除小鼠的胫骨软骨侵蚀比野生型小鼠少（P<0.02）。4周时，基因敲除小鼠的软骨性骨赘更大（P<0.01），但到8周时，骨赘的成熟度和大小与野生型小鼠无异。野生型和基因敲除小鼠关节中均出现X型胶原和DIPEN染色阳性的关节软骨细胞肥大。
我们的研究结果表明，OA小鼠模型中的结构性软骨损伤取决于MMP - 13活性。在该模型中，软骨细胞肥大不受MMP - 13活性调节，且其本身不会导致软骨侵蚀。在存在蛋白聚糖耗竭的情况下，MMP - 13缺乏可抑制软骨侵蚀，这支持了用MMP - 13抑制剂对已确诊的OA进行治疗干预的可能性。
