| First Author | Chavez RD | Year | 2019 |
| Journal | PLoS One | Volume | 14 |
| Issue | 1 | Pages | e0210601 |
| PubMed ID | 30629676 | Mgi Jnum | J:273269 |
| Mgi Id | MGI:6275841 | Doi | 10.1371/journal.pone.0210601 |
| Citation | Chavez RD, et al. (2019) Prg4 prevents osteoarthritis induced by dominant-negative interference of TGF-ss signaling in mice. PLoS One 14(1):e0210601 |
| abstractText | OBJECTIVE: Prg4, also known as Lubricin, acts as a joint/boundary lubricant. Prg4 has been used to prevent surgically induced osteoarthritis (OA) in mice. Surgically induced OA serves as a good model for post-traumatic OA but is not ideal for recapitulating age-related OA. Reduced expression of the TGF-beta type II receptor (TGFbetaR2) is associated with age-related OA in clinical samples, so we previously characterized a mouse model that exhibits OA due to expression of a mutated dominant-negative form of TGFbetaR2 (DNIIR). Prg4 expression was significantly reduced in DNIIR mice. Furthermore, we showed that Prg4 was a transcriptional target of TGF-ss via activation of Smad3, the main signal transducing protein for TGF-ss. The objective of the present study was to determine whether maintenance of Prg4, a down-stream transcriptional target of TGF-ss, prevents OA associated with attenuated TGF-ss signaling in mice. DESIGN: Wild-type, DNIIR, and bitransgenic mice that express both DNIIR and Prg4, were compared. Mice were assessed with a foot misplacement behavioral test, muCT, histology, and Western blot. RESULTS: Compared to DNIIR mice, bitransgenic DNIIR+Prg4 mice missed 1.3 (0.4, 2.1) fewer steps while walking (mean difference (95% confidence interval)), exhibited a cartilage fibrillation score that was 1.8 (0.4, 3.1) points lower, exhibited cartilage that was 28.2 (0.5, 55.9) mum thicker, and exhibited an OARSI score that was 6.8 (-0.9, 14.5) points lower. However, maintenance of Prg4 expression did not restore levels of phosphorylated Smad3 in DNIIR mice, indicating Prg4 does not simply stimulate TGF-ss signaling. CONCLUSIONS: Our results indicate that maintenance of Prg4 expression prevents OA progression associated with reduced TGF-beta signaling in mice. Since there was no evidence that Prg4 acts by stimulating the TGF-ss signaling cascade, we propose that Prg4, a transcriptional target of TGF-ss, attenuates OA progression through its joint lubrication function. |
