| First Author | Wang Y | Year | 2022 |
| Journal | Am J Pathol | Volume | 192 |
| Issue | 12 | Pages | 1683-1698 |
| PubMed ID | 36063901 | Mgi Jnum | J:332016 |
| Mgi Id | MGI:7407793 | Doi | 10.1016/j.ajpath.2022.08.003 |
| Citation | Wang Y, et al. (2022) Transforming Growth Factor-beta Receptor-Mediated, p38 Mitogen-Activated Protein Kinase-Dependent Signaling Drives Enhanced Myofibroblast Differentiation during Skin Wound Healing in Mice Lacking Hyaluronan Synthases 1 and 3. Am J Pathol 192(12):1683-1698 |
| abstractText | Normal myofibroblast differentiation is critical for proper skin wound healing. Neoexpression of alpha-smooth muscle actin (alpha-SMA), a marker for myofibroblast differentiation, is driven by transforming growth factor (TGF)-beta receptor-mediated signaling. Hyaluronan and its three synthesizing enzymes, hyaluronan synthases (Has 1, 2, and 3), also participate in this process. Closure of skin wounds is significantly accelerated in Has1/3 double-knockout (Has1/3-null) mice. Herein, TGF-beta activity and dermal collagen maturation were increased in Has1/3-null healing skin. Cultures of primary skin fibroblasts isolated from Has1/3-null mice had higher levels of TGF-beta activity, alpha-SMA expression, and phosphorylation of p38 mitogen-activated protein kinase at Thr180/Tyr182, compared with wild-type fibroblasts. p38alpha mitogen-activated protein kinase was a necessary element in a noncanonical TGF-beta receptor signaling pathway driving alpha-SMA expression in Has1/3-null fibroblasts. Myocardin-related transcription factor (MRTF), a cofactor that binds to the transcription factor serum response factor (SRF), was also critical. Nuclear localization of MRTF was increased, and MRTF binding to SRF was enhanced in Has1/3-null fibroblasts. Inhibition of MRTF or SRF expression by RNA interference suppresses alpha-SMA expression at baseline and diminished its overexpression in Has1/3-null fibroblasts. Interestingly, total matrix metalloproteinase activity was increased in healing skin and fibroblasts from Has1/3-null mice, possibly explaining the increased TGF-beta activation. |
