Abstract
ObjectivePrg4, 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-β type II receptor (TGFβR2) 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 TGFβR2 (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.DesignWild-type, DNIIR, and bitransgenic mice that express both DNIIR and Prg4, were compared. Mice were assessed with a foot misplacement behavioral test, μCT, histology, and Western blot.ResultsCompared 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) μm 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.ConclusionsOur results indicate that maintenance of Prg4 expression prevents OA progression associated with reduced TGF-β 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.
Highlights
The molecular mechanisms that control age-related osteoarthritis (OA) are not well defined
Our results indicate that maintenance of Prg4 expression prevents OA progression associated with reduced TGF-β 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
Summary
The molecular mechanisms that control age-related osteoarthritis (OA) are not well defined. The transforming growth factor beta (TGF-β) signaling pathway exhibits changes during age-related OA in humans. Human OA cartilage has been shown to exhibit reduced levels of the TGF-β type II receptor (TGFBR2) [1] and genetic variations in the SMAD3 gene are associated susceptibility to OA [2]. In young, healthy chondrocytes, TGF-β mainly signals through the TGF-β type I receptor (Tgfbr1/ALK5) and Smad2/3, whereas in aged mice, the level of an alternate type I receptor, Acvrl (ALK1), which uses Smad1/5, is increased [3, 4]. Chondroprotective targets of TGF-ß would be expected to have fewer side-effects than TGF-ß itself, which can have both positive and negative effects on cartilage that are often age dependent
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