{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T19:09:59Z","timestamp":1790622599865,"version":"4.1.0"},"reference-count":0,"publisher":"Cell Physiol Biochem Press GmbH and Co KG","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cell Physiol Biochem"],"abstract":"<jats:p>Background\/Aims: Muscle fibrosis and fatty infiltration (FI) are common complications seen in various muscle disease states. Recent studies indicate that muscle residential fibro\/adipogenic progenitors (FAPs) are the major cellular source for muscle fibrosis and FI. We previously showed that MMP13 knockout (KO) mice have significantly increased FI, suggesting an important role of MMP13 in muscle FI. However, how MMP13 affects the differentiation of FAPs remains unknown. Methods: In order to assess the role of MMP-13 on FAP differentiation, we isolated FAPs from wildtype C57BL\/6 and MMP13 knock out mice with FACS using CD31-, CD45-, Integrin \u03b17- and Sca-1+ markers. FAPs were cultured in 24 well plate after FACS.in standard media till 80% confluent and then switched to adipogenic medium. In order to study the role of TGF\u03b2 and BMP in their differentiation, FAPs from both wildtype and MMP13 KO mice were treated with TGF\u03b21 (5 ng\/ml). For MMP13 inhibitor treatment, FAPs from wildtype mice were incubated in adipogenic medium containing 10 \u00b5M MMP13 inhibitor (or vehicle) for 2 weeks. Immunofluorescence and gene expression analysis were used to assess FAP adipogenic and fibrogenic differentiation. FAPs were stained with Perilipin A (FITC, adipogenesis marker) and \u03b1SMA (Red, fibroblast marker), and DAPI. Real time PCR was performed for gene expression evaluation. A two-tailed Anova was used for statistical comparisons between groups, with p \u2264 0.05. Data are presented as mean \u00b1 standard deviation. Results: In this study, we isolated FAPs from wildtype C57BL\/6 and MMP13 KO mice and evaluated their adipogenic and fibrogenic differentiation in vitro . MMP13 KO FAPs demonstrated enhanced adipogenesis but reduced fibrogenesis compared to wildtype FAPs. Treating wildtype FAPs with an MMP13 inhibitor simulated phenotypes seen in MMP13 KO FAPs. In order to assess the role of MMP13 on TGF\u03b2\/BMP signaling in regulating FAP differentiation, we treated wildtype and MMP13 KO FAPs with TGF\u03b21, BMP7, TGF\u03b2 inhibitor, and BMP inhibitor. TGF\u03b21 treatment significantly enhanced fibrogenesis, but inhibited adipogenesis of wildtype FAPs. However, treatment with BMP7 showed the opposite effect. Interestingly, the effect of TGF\u03b21\/BMP7 was voided in MMP13 KO FAPs. Treating wildtype FAPs with MMP13 inhibitor also abolished the effect of TGF\u03b21\/BMP7 in FAP differentiation. Conclusion: Results from this study showed that TGF\u03b21 inhibits FAP adipogenesis but stimulates FAP fibrogenesis. BMP7 was shown to promote FAP adipogenesis but reduce its fibrogenesis. The role of the TGF\u03b2\/BMP signaling pathway regulating FAP differentiation was found to be MMP13 dependent. This study suggests that MMP13 is a critical downstream effector in TGF\u03b2\/BMP pathway which may serve as a new therapeutic target for muscle fibrosis and FI.<\/jats:p>","DOI":"10.33594\/000000596","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T08:08:23Z","timestamp":1671523703000},"page":"730-743","source":"Crossref","is-referenced-by-count":8,"title":["The Role of Matrix Metalloproteinase-13 (MMP13) in TGF\u03b2\/BMP Pathway Regulation of Fibro-Adipogenic Progenitor (FAP) Differentiation"],"prefix":"10.33594","volume":"56","author":[{"name":"San Francisco Veterans Affairs Health Care System, Department of Veterans Affairs, San Francisco, CA, USA","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Mengyao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"19235","published-online":{"date-parts":[[2022,12,20]]},"container-title":["Cellular Physiology and Biochemistry"],"original-title":[],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T08:08:26Z","timestamp":1671523706000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cellphysiolbiochem.com\/Articles\/000596\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,20]]},"references-count":0,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2022,12,20]]}},"URL":"https:\/\/doi.org\/10.33594\/000000596","relation":{},"ISSN":["1015-8987","1421-9778"],"issn-type":[{"value":"1015-8987","type":"print"},{"value":"1421-9778","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,20]]}}}