A new study published in Nature Communications identifies tankyrase, a poly-ADP-ribosyltransferase, as a regulator of cartilage anabolism and suggests that suppression of tankyrase activity contributes to restoration of cartilage matrix. The research could inform the development of new therapies for osteoarthritis (OA).

“OA development has been primarily associated with increased catabolic gene expression, such as genes encoding matrix-degrading enzymes. We think that our study suggests that stimulating the anabolic axis could serve as an approach to counter cartilage loss in OA and possibly to regenerate cartilage,” says corresponding author Jin-Hong Kim.

Tankyrase, encoded by TNKS or TNKS2, was previously known to be involved in various processes including WNT signalling and telomere maintenance. In the present study, transcriptome analysis in numerous strains of BXD mice revealed that tankyrase gene expression negatively correlated with expression of cartilage matrix genes. Knockdown of both Tnks and Tnks2 or treatment with tankyrase inhibitors induced the expression of cartilage matrix genes in mouse chondrocytes, suggesting that tankyrase inhibition promotes pro-anabolic pathways in cartilage.

The researchers also demonstrated that in human cartilage affected by OA, tankyrase expression is upregulated and inversely correlated with expression levels of type II collagen and aggrecan, compared with unaffected tissue. Consistent with these findings, expression of tankyrase in mouse knee joints was increased and that of aggrecan and the transcription factor SOX9 (a master regulator of chondrogenesis) decreased 8 weeks after surgery to induce post-traumatic OA.

In mouse chondrocytes, tankyrase inhibition inverted the expression patterns of OA-associated genes. In vivo, hydrogel-mediated intra-articular delivery of tankyrase inhibitors to the knees of mice with surgically induced OA protected against OA progression. This protective effect was associated with increased expression of cartilage matrix constituents, reduced production of catabolic regulators and preserved expression of SOX9 compared with vehicle administration only.

tankyrase inhibition promotes pro-anabolic pathways in cartilage

Tankyrase inhibition also enhanced the chondrogenic differentiation of human bone-marrow-derived mesenchymal stem cells and improved the regeneration of articular cartilage lesions.

Together, the findings could have implications for the development of therapies for OA aimed at cartilage regeneration.