Repression of lef1 displays reduced susceptibility to OA via impaired MMP13 expression

Purpose: As we age or undergo trauma to the joint, gradual loss of cartilage matrix is accompanied with an increase in metalloproteinase 13 (MMP13) expression, causing osteoarthritis (OA). We and others have established that deacetylase sirtuin-1 (SIRT1) displays reduced activity during OA, evoking MMP13 expression damage. Here attempt decipher molecular mechanism by which regulated, assessing effect Sirt1 on Lef1 latter being a known transcription factor required for expression. Methods: To assess mechanistic impact SIRT1 LEF1 human chondrocytes were stimulated pro-inflammatory cytokines monitored enrichment gene regulatory elements, via Chromatin immunoprecipitation (ChIP). further generated vivo mouse models, wherein genetically ablated cartilage-specific manner using ATCCre driver (ATCcreSirt1fl/fl ;ATCcreLef1fl/fl mice). ATCcreLef1fl/fl ATCcreSirt1fl/fl mice at embryonic day 17 (E17) compared controls (Lef1fl/fl Sirt1fl/fl, respectively), possible effects skeletal development. Next, 3 months from ATCcreSirt1fl /fl transgenes controls, subjected post-traumatic OA induction employing surgical Destabilization Medial Meniscus (DMM). Joint pain was assessed Pressure Application Measurement (PAM device) baseline (i.e. prior procedure) 8 weeks after sham DMM surgery. After sacrifice, joints graded severity, osteophyte formation, mineralized meniscus, levels synovitis inflammation. Results: In vitro data show inflammatory stimuli cause locus be enriched hyperacetylated H4K16, later associated inactivated higher N-terminal (NT) vs C-terminal (CT) per loci), enhanced transcription. Moreover, costal null exhibited increased Mmp13 transcription, while E17 embryos did not display any aberrant growth phenotype. age, severe lateral compartment Sirt1fl/fl mice. Additional hallmarks included meniscal mineralization, following DMM. On other hand, presented thresholds sensitivity as Lef1fl/fl DMM, possibly indicating less structural joint Conclusions: Overall, these multiple approaches represses prevent features. Lack SIRT1, its activity, may lift inhibitory permit characteristic lack LEF1, exhibit lesser pain, halting decline yet fully determined. Thus, inhibiting activating might constitute novel therapeutic interventions, maintain health, function related