Smad3 deficiency leads to mandibular condyle degradation via the sphingosine 1-phosphate (S1P)/S1P3 signaling axis.
Temporomandibular joint osteoarthritis is a degenerative disease that is characterized by permanent cartilage destruction. Transforming growth factor (TGF)-β is one of the most abundant cytokines in the bone matrix and is shown to regulate the migration of osteoprogenitor cells. It is hypothesized that TGF-β/Smad3 signaling affects cartilage homeostasis by influencing sphingosine 1-phosphate (S1P)/S1P receptor signaling and chondrocyte migration. We therefore investigated the molecular mechanisms by which crosstalk may occur between TGF-β/Smad3 and S1P/S1P receptor signaling to maintain condylar cartilage and to prevent temporomandibular joint osteoarthritis. Abnormalities in the condylar subchondral bone, including dynamic changes in bone mineral density and microstructure, were observed in Smad3(-/-) mice by microcomputed tomography. Cell-free regions and proteoglycan loss characterized the cartilage degradation present, and increased numbers of apoptotic chondrocytes and matrix metalloproteinase 13(+) chondrocytes were also detected. Furthermore, expression of S1P receptor 3 (S1P3), but not S1P1 or S1P2, was significantly down-regulated in the condylar cartilage of Smad3(-/-) mice. By using RNA interference technology and pharmacologic tools, S1P was found to transactivate Smad3 in an S1P3/TGF-β type II receptor-dependent manner, and S1P3 was found to be required for TGF-β-induced migration of chondrocyte cells and downstream signal transduction via Rac1, RhoA, and Cdc42. Taken together, these results indicate that the Smad3/S1P3 signaling pathway plays an important role in the pathogenesis of temporomandibular joint osteoarthritis.
Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Hiroki
H
Mori
Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan. Electronic address: tizawa@tokushima-u.ac.jp.
Takashi
T
Izawa
Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.
Eiji
E
Tanaka
D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D008335:Mandibular Condyle / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010003:Osteoarthritis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051900:Smad3 Protein / Q000172:deficiency / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors
D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D018125:Receptors, Transforming Growth Factor beta; C501285:S1pr3 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; C060506:sphingosine 1-phosphate; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D013110:Sphingosine