Novel roles for articular cartilage vesicles in osteoarthritis

Clement J. Zablocki Va Medical Center, Milwaukee WI

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Abstract

DESCRIPTION (provided by applicant): Articular cartilage matrix vesicles (ACVs) are small membrane-bound extracellular organelles found in normal cartilage and chondrocyte cultures. To date, they have almost exclusively been described in reference to their role in pathologic matrix mineralization in articular cartilage. Yet, their presence in normal cartilage and roles for ACVs other than mineral formation remain unexplored. We recently demonstrated that ACVs contain functional RNA and are able to transfer labeled RNA and protein to naove chondrocytes. The addition of 1-10 5g/ml normal ACVs to normal chondrocyte monolayers increased markers characteristic of the hypertrophic chondrocytes seen in osteoarthritic (OA) cartilage. These exciting findings suggest that ACVs directly interact with chondrocytes and may participate in the cellular changes seen in OA. Preliminary data suggest an important role for proteoglycans in binding ACVs to pericellular matrix. We hypothesize that increased activity of proteoglycan-degrading enzymes in early OA promotes ACV mobility and fosters ACV-chondrocyte interactions in cartilage. However, the mechanisms through which ACVs bind to matrix components and the identity of the factors modulating matrix binding are unstudied. Similarly, little is known about the factors that mediate the cellular effects of ACVs. Exposure of normal articular chondrocytes to exogenous transglutaminase (Tgase) enzymes promotes chondrocyte hypertrophy in an integrin-dependent manner. As Tgases are present in high levels in ACVs, we hypothesize that Tgases in or on ACVs are responsible for inducing the hypertrophic phenotype in chondrocytes exposed to ACVs and that this effect is integrin-dependent. Using porcine ACV and chondrocytes, and replicating key experiments with ACVs from purchased human chondrocytes, we will investigate the following hypotheses: Specific aim 1: To investigate the hypothesis that ACVs bind to proteoglycans in matrix and ADAMTS4 and 5 release ACVs from cartilage matrix. Specific aim 2: To investigate the hypothesis that Tgases in ACVs are responsible for induction of the hypertrophic phenotype seen in chondrocytes after ACV exposure and that this is integrin-dependent. The ultimate goal of this work is to understand the role of ACVs in cartilage in the hope that manipulating the contents or availability of these organelles might contribute to the treatment of OA.