Abstract
Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. Despite efforts to reconstruct cartilage matrix in osteoarthritic joints, it has been a difficult task as adult cartilage exhibits marginal repair capacity. Here we report the identification of tankyrase as a regulator of the cartilage anabolism axis based on systems-level factor analysis of mouse reference populations. Tankyrase inhibition drives the expression of a cartilage-signature matrisome and elicits a transcriptomic pattern that is inversely correlated with OA progression. Furthermore, tankyrase inhibitors ameliorate surgically induced OA in mice, and stem cell transplantation coupled with tankyrase knockdown results in superior regeneration of cartilage lesions. Mechanistically, the pro-regenerative features of tankyrase inhibition are mainly triggered by uncoupling SOX9 from a poly(ADP-ribosyl)ation (PARylation)-dependent protein degradation pathway. Our findings provide insights into the development of future OA therapies aimed at reconstruction of articular cartilage.
Highlights
Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix
Recent progress in the understanding of the pathophysiology of OA has led to the identification of promising therapeutic targets, highlighting the potential for the development of diseasemodifying osteoarthritis drugs (DMOADs)[48,49,50,51,52,53,54,55,56,57]
The identification of MMP1358 and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5)[55,56] as destructive enzymes for type II collagen and aggrecan led to the active investigation of drugs that may delay OA advancement through the erosion of cartilage matrix[59,60]
Summary
Osteoarthritis (OA) is a prevalent degenerative disease, which involves progressive and irreversible destruction of cartilage matrix. To compensate for the lack of intrinsic repairing abilities, stem cell-based therapies relying on the enrichment of mesenchymal stem cell (MSC) population via marrow stimulation or direct transplantation into the damaged region have been widely attempted[6,7,8] These cells, tend to rapidly lose chondrogenic features after their differentiation, accompanied with the cessation of cartilage matrix molecule synthesis[9]. Tankyrase interacts with target proteins through their unique ankyrin repeat protein-interaction domain and catalyzes the addition of ADPribose moieties onto target proteins by using NAD+ as the substrate[24] This post-translational modification process, termed as poly(ADP-ribosyl)ation (PARylation), is known to regulate the activity and stability of substrate proteins[22]. Several highly specific and potent tankyrase inhibitors are available that may provide opportunities to develop therapies to modulate tankyrase activity[24]
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