Accelerated, aging-dependent development of osteoarthritis in alpha 1 integrin-deficient mice

• Published in: Arthritis and rheumatism 2003-10, Vol.48 (10), p.2873-2880
• Main Authors: Zemmyo, M, Meharra, E J, Kuhn, K, Creighton-Achermann, L, Lotz, M
• Format: Article
• Language: English
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.11246

Cell-matrix interactions regulate chondrocyte differentiation and survival. The alpha 1 beta 1 integrin is a major collagen receptor that is expressed on chondrocytes. Mice with targeted inactivation of the integrin alpha 1 gene ( alpha 1-KO mice) provide a model that can be used to address the role of cell-matrix interactions in cartilage homeostasis and osteoarthritis (OA) pathogenesis. Knee joints from alpha 1-KO and wild-type (WT) BALB/c mice were harvested at ages 4-15 months. Knee joint sections were examined for inflammation, cartilage degradation, and loss of glycosaminoglycans (by Safranin O staining). Immunohistochemistry was performed to detect the distribution of alpha 1 integrin, matrix metalloproteinases (MMPs), and chondrocyte apoptosis. In WT mice, the alpha 1 integrin subunit was detected in hypertrophic chondrocytes in the growth plate and in a subpopulation of cells in the deep zone of articular cartilage. There was a marked increase in alpha 1-positive chondrocytes in the superficial and upper mid-zones in OA-affected areas in joints from old WT mice. The alpha 1-KO mice showed more severe cartilage degradation, glycosaminoglycan depletion, and synovial hyperplasia as compared with the WT mice. MMP-2 and MMP-3 expression was increased in the OA-affected areas. In cartilage from alpha 1-KO mice, the cellularity was reduced and the frequency of apoptotic cells was increased. These results suggest that the alpha 1 integrin subunit is involved in the early remodeling process in OA cartilage. Deficiency in the alpha 1 integrin subunit is associated with an earlier deregulation of cartilage homeostasis and an accelerated, aging-dependent development of OA.