Accelerated, aging-dependent development of osteoarthritis in alpha1 integrin-deficient mice.
OBJECTIVE
Cell-matrix interactions regulate chondrocyte differentiation and survival. The alpha1beta1 integrin is a major collagen receptor that is expressed on chondrocytes. Mice with targeted inactivation of the integrin alpha1 gene (alpha1-KO mice) provide a model that can be used to address the role of cell-matrix interactions in cartilage homeostasis and osteoarthritis (OA) pathogenesis.


METHODS
Knee joints from alpha1-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 alpha1 integrin, matrix metalloproteinases (MMPs), and chondrocyte apoptosis.


RESULTS
In WT mice, the alpha1 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 alpha1-positive chondrocytes in the superficial and upper mid-zones in OA-affected areas in joints from old WT mice. The alpha1-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 alpha1-KO mice, the cellularity was reduced and the frequency of apoptotic cells was increased. These results suggest that the alpha1 integrin subunit is involved in the early remodeling process in OA cartilage.


CONCLUSIONS
Deficiency in the alpha1 integrin subunit is associated with an earlier deregulation of cartilage homeostasis and an accelerated, aging-dependent development of OA.
Zemmyo
Michihisa
M
The Scripps Research Institute, La Jolla, California, USA.
Meharra
E John
EJ
Kühn
Klaus
K
Creighton-Achermann
Lilo
L
Lotz
Martin
M
D000375:Aging / Q000502:physiology*; D000818:Animals; D002356:Cartilage / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D005109:Extracellular Matrix / Q000201:enzymology / Q000473:pathology; D005260:Female; D006706:Homeostasis / Q000502:physiology; D039423:Integrin alpha1 / Q000235:genetics*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000473:pathology / Q000503:physiopathology*; D012720:Severity of Illness Index
D039423:Integrin alpha1; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2