Prg4 prevents osteoarthritis induced by dominant-negative interference of TGF-ss signaling in mice

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 (TGF beta R2) 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 TGF beta R2 (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, mu CT, 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) mu m 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.