Type XI collagen is believed to play important roles in controlling the microstructural organization and composition of articular cartilage during growth and maturation. The long-term objective of this project is to determine how a type XI collagen gene mutation contributes to articular cartilage inflammation and destruction in osteoarthritis (OA). Mice heterozygous for a mutated sequence in the Coillal gene appear developmentally normal, but develop premature onset of OA characterized by severe cartilage erosion and joint inflammation (Li et al., 1995). Our preliminary studies demonstrate that this collagen defect gives rise to a local decrease in cartilage stiffness and associated local expression of joint OA. Thus, we hypothesize that mechanical factors initiate OA in this model, through structural and functional changes that expose the cartilage extracellular matrix to altered stresses and strains upon loading. We propose a mechanism for the mechanical induction of OA in this transgenic mouse model, whereby type XI collagen insufficiency leads to changes in cartilage tensile properties associated with modifications in collagen fiber organization and changes in cartilage compressive properties associated with modified proteoglycan content. We further propose that the type XI collagen gone mutation affects the more highly organized regions of mouse articular cartilage, i.e., superficial zone cartilage. Studies of knee and hip joint cartilage will be performed at 1-month of age, to quantify early changes that may predispose the joints to OA. Cartilage tensile properties will be quantified using an osmotic loading method, and the orientation of the collagen microstructure will be measured using optical birefringence. Cartilage compressive properties will be quantified with indentation tests, and negative fixed charge density will be measured from densitometric measures of Safranin-O staining. To characterize the time course of cartilage destruction in the wild-type and mutant joints, we will quantify histomorphometric grade, serum levels of OA biomarkers (COMP, 5D4), and cartilage protein expression and mRNA levels for proteinases (MMP-2, MMP-3, MMP-9, MMP-13,aggrecanases), cytokines (IL-1, IL-6, TNF-alpha) and precursors to inflammatory mediators (NOS2,COX2). Completion of this study will document the temporal expression of functional changes in the cartilage matrix, and corresponding changes in proteolytic activity and inflammation in the onset and progression of OA in vivo.
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