Abstract
Mutation or loss of collagen VI has been linked to a variety of musculoskeletal abnormalities, particularly muscular dystrophies, tissue ossification and/or fibrosis, and hip osteoarthritis. However, the role of collagen VI in bone and cartilage structure and function in the knee is unknown. In this study, we examined the role of collagen VI in the morphology and physical properties of bone and cartilage in the knee joint of Col6a1−/− mice by micro-computed tomography (microCT), histology, atomic force microscopy (AFM), and scanning microphotolysis (SCAMP). Col6a1−/− mice showed significant differences in trabecular bone structure, with lower bone volume, connectivity density, trabecular number, and trabecular thickness but higher structure model index and trabecular separation compared to Col6a1+/+ mice. Subchondral bone thickness and mineral content increased significantly with age in Col6a1+/+ mice, but not in Col6a1−/− mice. Col6a1−/− mice had lower cartilage degradation scores, but developed early, severe osteophytes compared to Col6a1+/+mice. In both groups, cartilage roughness increased with age, but neither the frictional coefficient nor compressive modulus of the cartilage changed with age or genotype, as measured by AFM. Cartilage diffusivity, measured via SCAMP, varied minimally with age or genotype. The absence of type VI collagen has profound effects on knee joint structure and morphometry, yet minimal influences on the physical properties of the cartilage. Together with previous studies showing accelerated hip osteoarthritis in Col6a1−/− mice, these findings suggest different roles for collagen VI at different sites in the body, consistent with clinical data.
Highlights
Collagen VI is heterotrimeric protein consisting of three different a-chains: a1(VI), a2(VI), and a3(VI)
A susceptibility locus for atopic dermatitis was identified in COL6A5 [18] and the DVWA susceptibility locus for knee osteoarthritis identified as part of COL6A4 [19,20]
Immunohistochemistry staining confirmed that collagen VI was present in the pericellular matrix (PCM) of Col6a1+/+ cartilage and was absent from Col6a12/2 cartilage (Figure 1); in the Col6a1+/+tibia, the growth plate showed significant labeling for collagen VI
Summary
Collagen VI is heterotrimeric protein consisting of three different a-chains: a1(VI), a2(VI), and a3(VI). Recent research has identified three other collagen VI subunits, a4(VI), a5(VI), and a6(VI), which may substitute in place of a3(VI) in the heterotrimeric fibrils [6,7]. Human collagen VI genetic abnormalities have been linked to muscular disorders, Bethlem myopathy, Ullrich congenital muscular dystrophy and congenital myosclerosis [8,9,10,11], and to ligamentous disorders, namely ossification of the ligamentum flavum, ossification of the posterior longitudinal ligament of the spine, and diffuse idiopathic skeletal hyperostosis [12,13,14]. Mutations in collagen VI genes have been linked to mitochondrial dysfunction [15], to abnormal expression of proteoglycans and adhesion molecules in some tissues [16,17], and to a skin disorder, atopic dermatitis [7]. A susceptibility locus for atopic dermatitis was identified in COL6A5 [18] and the DVWA (double von Willebrand factor A domains) susceptibility locus for knee osteoarthritis identified as part of COL6A4 [19,20]
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