title: ROCK/actin/MRTF signaling promotes the fibrogenic phenotype of fibroblast-like synoviocytes derived from the temporomandibular joint.
abstract: Malocclusion caused by abnormal jaw development or muscle overuse during mastication results in abnormal mechanical stress to the tissues surrounding the temporomandibular joint (TMJ). Excessive mechanical stress against soft and hard tissues around the TMJ is involved in the pathogenesis of inflammatory diseases, including osteoarthritis (OA). OA-related fibrosis is a possible cause of joint stiffness in OA. However, cellular and molecular mechanisms underlying fibrosis around the TMJ remain to be clarified. Here, we established a cell line of fibroblast‑like synoviocytes (FLSs) derived from the mouse TMJ. Then, we examined whether the Rho‑associated coiled‑coil forming kinase (ROCK)/actin/myocardin-related transcription factor (MRTF) gene regulatory axis positively regulates the myofibroblast (MF) differentiation status of FLSs. We found that i) FLSs extensively expressed the MF markers α‑smooth muscle actin (α‑SMA) and type I collagen; and ii) an inhibitor against the actin‑polymerizing agent ROCK, Y‑27632; iii) an actin-depolymerizing agent cytochalasin B; iv) an inhibitor of the MRTF/serum response factor‑regulated transcription, CCG‑100602, clearly suppressed the mRNA levels of α‑SMA and type I collagen in FLSs; and v) an MF differentiation attenuator fibroblast growth factor‑1 suppressed filamentous actin formation and clearly suppressed the mRNA levels of α-SMA and type I collagen in FLSs. These results strongly suggest that the ROCK/actin/MRTF axis promotes the fibrogenic activity of synoviocytes around the TMJ. Our findings partially clarify the molecular mechanisms underlying the emergence of TMJ‑OA and may aid in identifying drug targets for treating this condition at the molecular level.
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yokota
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Chosa
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Kyakumoto
authors.affiliation: Division of Orthodontics, Department of Developmental Oral Health Science, Iwate Medical University, Iwate 020‑8505, Japan.
authors.forename: Hitomichi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Ibi
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Kamo
authors.affiliation: Division of Orthodontics, Department of Developmental Oral Health Science, Iwate Medical University, Iwate 020‑8505, Japan.
authors.forename: Kazuro
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Division of Cellular Biosignal Sciences, Department of Biochemistry, Iwate Medical University, Iwate 028‑3694, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ishisaki
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D005260:Female; D008310:Malocclusion / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013314:Stress, Mechanical; D000070918:Synoviocytes / Q000378:metabolism* / Q000473:pathology; D013704:Temporomandibular Joint / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000378:metabolism*; D054460:rho-Associated Kinases
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D015534:Trans-Activators; D054460:rho-Associated Kinases