Cartilage-like composition of keloid scar extracellular matrix suggests fibroblast mis-differentiation in disease

Following wound damage to the skin, the scarring spectrum is wide-ranging, from a manageable normal scar through to pathological keloids. The question remains whether these fibrotic lesions represent simply a quantitative extreme, or alternatively, whether they are qualitatively distinct. A three-way comparison of the extracellular matrix (ECM) composition of normal skin, normal scar and keloids was performed using quantitative discovery-based proteomics. This approach identified 40 proteins that were significantly altered in keloids compared to normal scars, and strikingly, 23 keloid-unique proteins. The major alterations in keloids, when functionally grouped, showed many changes in proteins involved in ECM assembly and fibrillogenesis, but also a keloid-associated loss of proteases, and a unique cartilage-like composition, which was also evident histologically. The presence of Aggrecan and Collagen II in keloids suggest greater plasticity and mis-differentiation of the constituent cells. This study characterises the ECM of both scar types to a depth previously underappreciated. This thorough molecular description of keloid lesions relative to normal scars is an essential step towards our understanding of this debilitating clinical problem, and how best to treat it. •Keloid extracellular matrix (ECM) is qualitatively distinct from normal scar matrix.•Keloid lesions have unique expression of SLRPs and FACIT collagens, which could affect ECM organization and stability.•Keloid lesions inappropriately express Aggrecan and Collagen II, ECM proteins typically associated with cartilage.•The cartilage-like tissue phenotype suggests heightened fibroblast plasticity and misdifferentiation in disease.•These findings highlight molecular targets for the therapeutic disruption of the scarred ECM architecture.