Title: Attenuation of the Progression of Articular Cartilage Degeneration by Inhibition of Tgf-β1 Signaling in a Mouse Model of Osteoarthritis
Description: Background: The goal of this study is to understand role of transforming growth factor beta 1 (TGF-β1) in development of osteoarthritis (OA). Results from studies indicate that the genetic inactivation of Smad-3, or the disruption of the interaction of Tgf-β1 with its receptor Tgf-β type II receptor (Tgfbr2), in germline cells results in OA-like knee joints in mice at one month of age. However, other studies suggest that the increased expression of Tgf-β1 in mature knee joints causes OA in animal models. A human genetic study reports that a two-nucleotide deletion, 741-742del AT, and/or a nucleotide change, 859C>T or 782C>T in SMAD-3 are associated with early-onset OA. This observation is consistent with the finding that the lack of Tgf-β1 signaling in the germline cell results in OA in developing joints and that increased Tgf-β1 signaling causes OA in mature joints. The plausible explanation for this “conflicting” role of TGF-β1 in the pathogenesis of OA is that the effective TGF-β1 signaling acts in either a dose-dependent or a developmental stage-dependent manner. The present study addresses the question as to whether inhibition of Tgf-β1 signaling prevents mature knee joints from being degenerated in mouse models of OA.

Methods: 1) Using conditional knock out techniques with aggrecan-CreERt2 mice and floxed Tgfbr2 mice, Tgfbr2 was removed from articular cartilage of knee joints in 2-month-old mice. Mice without Tgfbr2 were kept for another 6 months or longer. Knee joints from the mice (n=8) and their corresponding control (n=4) were collected for morphological analysis.

2) Mice without Tgfbr2 at two months old were subjected to DMM to induce articular cartilage degeneration. Knee joints from the mice at 4 and 8 weeks post surgery (n=8 in each group) were collected for morphological analysis.

Results: 1) We did not find the initiation and acceleration of articular cartilage degeneration by the genetic inactivation of Tgfbr2 in knee joints of mice at the age of 9 months or older. We also did not find hypertrophic chondrocytes in the articular cartilage of the mice.

2) We found that removal of Tgfbr2 in articular cartilage of knee joints delayed articular cartilage degeneration, at least 6 weeks, compared to that in wild-type littermates.

Conclusion: Inhibition of Tgf-β1 signaling attenuated articular cartilage degeneration in mature knee joints of mouse models of OA. Therefore, inhibition activity of TGF-β1, not application of TGF-β1, may be considered in treatment of OA in mature joints.