Targeting Molecular Collagen Defects from the Initiation of Knee Osteoarthritis

Knee osteoarthritis (OA) is the most prevalent degenerative joint disease. When morphological changes become apparent on radiographs, no approved treatment can reverse the disease process. Early diagnosis is an unmet need demanding new molecular and imaging biomarkers to define OA from the earliest stages. In this context, we focus on collagen, the most basic building block of all joint tissues, and interrogate how OA development affects collagens molecular folding, a previously underexplored area. Here, through whole-joint mapping with a peptide that recognizes unfolded collagen molecules, we report the discovery of collagen denaturation in cartilage before proteolysis and major histopathological degeneration in animal models and patients. Mechanistically, we reveal that such molecular collagen defects can be driven by mechanical overloading without collagenase degradation and are intimately associated with glycosaminoglycan loss. We showcase the advantages of using collagen denaturation as an early-stage OA hallmark for in vivo therapeutic evaluation and molecular magnetic resonance imaging (MRI) of subtle joint defects that are challenging to detect with conventional morphology-based MRI. These results highlight biomolecular integrity as a crucial dimension for characterizing joint degeneration and a molecular foundation for diagnosing early-stage OA and beyond.