Identification of α2‐Macroglobulin as a Master Inhibitor of Cartilage‐Degrading Factors That Attenuates the Progression of Posttraumatic Osteoarthritis

Abstract

ObjectiveTo determine if supplemental intraarticular α2‐macroglobulin (α2M) has a chondroprotective effect in a rat model of osteoarthritis (OA).MethodsUsing Western blotting, mass spectrometry, enzyme‐linked immunosorbent assay (ELISA), and immunohistochemistry, α2M was identified as a potential therapeutic agent through a comparison of α2M concentrations in serum, synovial fluid (SF), and cartilage from normal subjects and patients with OA. In cultured chondrocytes, the effects of α2M 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 α2M, 3) ACLT and 2 IU/kg injections of α2M, 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.ResultsIn both normal subjects and OA patients, α2M 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, α2M 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 α2M reduced the concentration of MMP‐13 in SF, had a favorable effect on OA‐related gene expression, and attenuated OA progression.ConclusionThe plasma protease inhibitor α2M is not present in sufficient concentrations to inactivate the high concentrations of catabolic factors found in OA SF. Our findings suggest that supplemental intraarticular α2M provides chondral protection in posttraumatic OA.