Identification of α2 -Macroglobulin as a Master Inhibitor of Cartilage-Degrading Factors That Attenuates the Progression of Posttraumatic Osteoarthritis.
Arthritis Rheumatol. 2014 Jul;66(7):1843-53. doi: 10.1002/art.38576.
Identification of α2 -Macroglobulin as a Master Inhibitor of
Cartilage-Degrading Factors That Attenuates the Progression of
Wang S1, Wei X, Zhou J, Zhang J, Li K, Chen Q, Terek R, Fleming BC, Goldring MB, Ehrlich MG, Zhang G, Wei L.
To determine if supplemental intraarticular α2 -macroglobulin (α2 M) has a chondroprotective effect in a
rat model of osteoarthritis (OA).
Using Western blotting, mass spectrometry, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry, α2 M was identified as a potential therapeutic agent through a comparison of α2 M concentrations in serum, synovial fluid (SF), and cartilage from normal subjects and patients with OA.
In cultured chondrocytes, the effects of α2 M on interleukin-1 (IL-1)-induced cartilage catabolic enzymes were evaluated by Luminex assay and ELISA. In vivo effects on cartilage degeneration and matrix metalloproteinase 13 (MMP-13) concentration were evaluated in male rats (n = 120) randomized to 1 of 4 treatments: 1) anterior cruciate ligament transection (ACLT) and saline injections, 2) ACLT and 1 IU/kg injections of α2 M, 3) ACLT and 2 IU/kg injections of α2 M, or 4) sham operation and saline injections.
Rats were administered intraarticular injections for 6 weeks. The concentration of MMP-13 in SF lavage fluid was measured using ELISA. OA-related gene expression was quantified by real-time quantitative polymerase chain reaction. The extent of OA progression was graded by histologic examination.
In both normal subjects and OA patients, α2 M levels were lower in SF as compared to serum, and in OA patients, MMP-13 levels were higher in SF than in serum. In vitro, α2 M inhibited the induction of MMP-13 by IL-1 in a dose-dependent manner in human chondrocytes. In the rat model of ACLT OA, supplemental intraarticular injection of α2 M reduced the concentration of MMP-13 in SF, had a favorable effect on OA-related gene expression, and attenuated OA progression.
The plasma protease inhibitor α2 M is not present in sufficient concentrations to inactivate the high concentrations of catabolic factors found in OA SF. Our findings suggest that supplemental intraarticular α2 M provides chondral protection in posttraumatic OA.
Copyright © 2014 by the American College of Rheumatology.