A high-impact COL6A3 mutation alters the response of chondrocytes in neo-cartilage organoids to hyper-physiologic mechanical loading

Dysregulation of mechano-transduction via chondrocyte pericellular matrix (PCM) has been shown to induce osteoarthritis (OA), a highly prevalent degenerative disease of joint tissues. By performing exome sequencing in symptomatic OA patients, a high impact mutation in COL6A3 encoding one of the monomeric sub-unit-3 of collagen type VI (COLVI) was identified. COLVI is an essential and specific protein functioning in the PCM. To study the downstream effects of the mutation in interaction with hyper-physiologic mechanical loading conditions, genetically COL6A3-edited human induced pluripotent stem cells (hiPSCs) were employed in our established in-vitro cartilage organoid model. We showed mutated COLVI had significant lower binding to fibronectin (FN) and provoked an osteoarthritic chondrocyte state. Moreover, the COL6A3 mutation abolished the initial stress responses of chondrocytes to hyper-physiological mechanical loading conditions. Together, the established sustainable cartilage organoid model provides unique opportunities to study the transduction of mechanical cues to chondrocytes and explore ways to counteract effects.Acquired insights could guide effective treatment development for OA.