BioProject

Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. More...

Injuries to flexor tendons can be complicated by fibrotic adhesions, which severely impair the function of the hand. Adhesions have been associated with PAI-1, a master suppressor of protease activity including matrix metalloproteinases (MMP). In the present study, we used next generation RNA sequencing (RNA-seq) to assess genome-wide differences in mRNA expression due to PAI-1 deficiency after zone II flexor tendon injury. Ingenuity pathway analysis was used to characterize molecular pathways and biological drivers associated with differentially expressed genes. Analysis of hundreds of overlapping and differentially-expressed genes in PAI-1 knockout and C57Bl/6J mice during tendon healing revealed common and distinct biological processes associated with the regulation of matrix organization, cell cycle, and immune response. Most importantly, we identified the activation of PTEN signaling and the inhibition of FOXO1-associated biological processes as a unique transcriptional signature of the healing tendon in the PAI-1 KO mice. The differences in transcriptomics between the two mouse strains are transcriptionally related to complex cross-talk between PI3K/Akt/mTOR, PKC, and MAPK signaling cascades that drive differences in transcriptional regulation of cell proliferation, survival and senescence, and chronic inflammation as potential drivers of fibrotic healing and adhesions in the C57Bl/6J injured tendons. These transcriptional observations should guide future studies to develop an improved understanding of the biological limitations of tendon healing as the basis for rational design of targeted therapeutics for scar-free regenerative healing of tendon. Overall design: Tendon tissue (n = 3 per group) was harvested from uninjured, 2-weeks, and 4-weeks post injury tendons of WT and PAI-1 KO mice Less...