p21^−/− Mice Exhibit Spontaneous Articular Cartilage Regeneration Post-Injury

Abstract

Objective Recent studies have implicated the cyclin dependent kinase inhibitor, p21, in enhanced tissue regeneration observed in MRL/MpJ “super-healer” mice. Specifically, p21 is downregulated in MRL cells and similar ear hole closure to MRL mice has been observed in p21−/− mice. However, the direct implications of p21 deletion in endogenous articular cartilage regeneration remain unknown. In this study, we investigated the role of p21 deletion in the ability of mice to heal full-thickness cartilage defects (FTCDs). Design C57BL/6 and p21−/− ( Cdkn1atm1Tyj) mice were subjected to FTCD and assessment of cartilage healing was performed at 1 hour, 3 days, 1 week, 2 weeks, and 4 weeks post-FTCD using a 14-point histological scoring system. X-ray microscopy was used to quantify cartilage healing parameters (e.g., cartilage thickness, surface area/volume) between C57BL/6 and p21−/− mice. Results Absence of p21 resulted in increased spontaneous articular cartilage regeneration by 3 days post-FTCD. Furthermore, p21−/− mice presented with increased cartilage thickness at 1 and 2 weeks post-FTCD compared with uninjured controls, returning to baseline by 4 weeks post-FTCD. Conclusions We report that p21−/− mice display enhanced articular cartilage regeneration post-FTCD compared with C57BL/6 mice. Furthermore, cartilage thickness was increased in p21−/− mice at 1 week post-FTCD compared with uninjured p21−/− mice and C57BL/6 mice.

Altered TGFB1 regulated pathways promote accelerated tendon healing in the superhealer MRL/MpJ mouse

“…Furthermore, the antifibrotic agent used to treat IPF, Pirfenidone, has been shown to induce cell cycle arrest 49 , 50 . Reduced cell apoptosis, cell cycle regulation through p21 ( cdkn1a ) 51 , p53 ( trp53 ), and p16 ( cdkn2a ), increased cell proliferation 52 , and enhanced stem cell function 53 may command augmented regenerative capacity.…”

Understanding cartilage protection in OA and injury: a spectrum of possibilities

“…Later, the enhanced healing potential of through-and-through ear injuries was observed in p21 knockout (p21 −/− ) mice, suggesting the lack of p21 is at least partially responsible for the enhanced regenerative phenotype seen in MRL/MpJ mice [48]. This has been further corroborated by recent findings implicating p21 deletion in articular cartilage regeneration [49]. However, the involvement of p21 in other intricate cellular processes, such as apoptosis [50] and inflammation [51], in addition to its tight regulation, hinders our ability to elucidate the exact mechanisms associated with the healing phenotype seen after its deletion [52].…”

“…Interestingly, the "super-healer" MRL/MpJ mice are resistant to cartilage damage and show reduced severity of PTOA when compared to C57BL/6 mice, whether following surgical DMM [22] or non-surgical IAF [88]. Similar results are seen in the LG/J strain [34], whereas p21 −/− mice seem to be vulnerable to cartilage damage following DMM surgery [89], despite its superior regenerative potential after full-thickness cartilage injury [49].…”

Altered TGFB1 regulated pathways promote accelerated tendon healing in the superhealer MRL/MpJ mouse

“…Furthermore, the antifibrotic agent used to treat IPF, Pirfenidone, has been shown to induce cell cycle arrest (Ruwanpura et al, 2020, Sun et al, 2018, Usugi et al, 2019). Reduced cell apoptosis, cell cycle regulation through p21 ( cdkn1a )(Jablonski et al, 2019, Bedelbaeva et al, 2010), p53 ( trp53 ), and p16 ( cdkn2a ), increased cell proliferation(Bedelbaeva et al, 2010), and enhanced stem cell function(Naviaux et al, 2009) may command augmented regenerative capacity. Given that PTEN, a tumor suppressor gene, is a natural inhibitor of the phosphoinositide 3-kinase (PI3K) and of the mammalian target of rapamycin (mTOR) pathway, the negative enrichment of PTEN regulated genes provide a mechanistic link between mTOR-regulated cell cycle and scar healing in tendon.…”