Background The D prostanoid receptor 1 (DP1), a receptor for prostaglandin D2 (PGD2) plays important roles in inflammation and cartilage metabolism. However, its role in the pathogenesis of osteoarthritis (OA) remains unknown.
Objectives We undertook this study to explore the roles of DP1 in the development of OA and to evaluate the efficacy of a DP1 selective agonist in the treatment of OA.
Methods We compared the development of aging-associated OA and destabilization of the medial meniscus (DMM)-induced OA in DP1-deficient (DP1-/-) and wild-type (WT) mice. The progression of OA was assessed by histology, immunohistochemistry, and microcomputed tomography (micro-CT). Cartilage explants from DP1-/- and WT mice were treated with interleukin-1α (IL-1α) ex vivo, to evaluate proteoglycan degradation. The effect of intra-peritoneal administration of the DP1 selective agonist BW245C on OA progression was evaluated in WT mice.
Results Compared to WT mice, DP1-/- mice had exacerbated cartilage degradation in both models of OA and this was associated with increased expression of MMP-13, and ADAMTS-5. In addition, DP1-/- mice demonstrated enhanced subchondral bone changes. Cartilage explants from DP1-/- mice showed enhanced proteoglycan degradation following treatment with IL-1α. Intraperitoneal injection of BW245C attenuated the severity of DMM-induced cartilage degradation and bony changes in WT mice.
Conclusions These findings indicate a critical role for DP1 signaling in OA pathogenesis. Modulation of DP1 functions may constitute a potential therapeutic target for the development of novel OA treatments.
Acknowledgements This work was supported by the Canadian Institutes of Health Research (CIHR) Grant MOP-130293, the Arthritis Society, and the Fonds de la Recherche du Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM).
Disclosure of Interest None declared