Deletion of Dual Specificity Phosphatase 1 Does Not Predispose Mice to Increased Spontaneous Osteoarthritis

Abstract

BackgroundOsteoarthritis (OA) is a degenerative joint disease with poorly understood etiology and pathobiology. Mitogen activated protein kinases (MAPKs) including ERK and p38 play important roles in the mediation of downstream pathways involved in cartilage degenerative processes. Dual specificity phosphatase 1 (DUSP1) dephosphorylates the threonine/serine and tyrosine sites on ERK and p38, causing deactivation of downstream signalling. In this study we examined the role of DUSP1 in spontaneous OA development at 21 months of age using a genetically modified mouse model deficient in Dusp1 (DUSP1 knockout mouse).ResultsUtilizing histochemical stains of paraffin embedded knee joint sections in DUSP1 knockout and wild type female and male mice, we showed similar structural progression of cartilage degeneration associated with OA at 21 months of age. A semi-quantitative cartilage degeneration scoring system also demonstrated similar scores in the various aspects of the knee joint articular cartilage in DUSP1 knockout and control mice. Examination of overall articular cartilage thickness in the knee joint demonstrated similar results between DUSP1 knockout and wild type mice. Immunostaining for cartilage neoepitopes DIPEN, TEGE and C1,2C was similar in the cartilage lesion sites and chondrocyte pericellular matrix of both experimental groups. Likewise, immunostaining for phosphoERK and MMP13 showed similar intensity and localization between groups. SOX9 immunostaining demonstrated a decreased number of positive cells in DUSP1 knockout mice, with correspondingly decreased staining intensity. Analysis of animal walking patterns (gait) did not show a discernable difference between groups.ConclusionLoss of DUSP1 does not cause changes in cartilage degeneration and gait in a mouse model of spontaneous OA at 21 months of age. Altered staining was observed in SOX9 immunostaining which may prove promising for future studies examining the role of DUSPs in cartilage and OA, as well as models of post-traumatic OA.

Dual-specificity MAP kinase phosphatases in health and disease

“…Finally, given its key role as a critical regulator of innate and adaptive immunity ( Table 2 ), loss of DUSP1 /MKP-1 was also found to exacerbate a range of inflammatory phenotypes in mouse models including experimental colitis [ 40 ], anaphylaxis [ 41 ] and psoriasis [ 42 ], However, for reasons as yet unclear, loss of DUSP1 /MKP-1 did not sensitize mice to the development of spontaneous age-dependent osteoarthritis, despite the involvement of an inflammatory process and mediators such as TNFα and interleukin-1β in this disease [ 43 ]. DUSP1 /MKP-1 is also directly targeted by a range of immune modulators.…”

Role of Dual-Specificity Phosphatase 1 in Glucocorticoid-Driven Anti-inflammatory Responses

“…However, DUSP1 depletion did not affect age-related spontaneously occurring osteoarthritis, since knockout mice showed a similar disease progression compared to controls at 21 months of age (54). Thus, the modulatory function of DUSP1 in the context of bone homeostasis seems to be most evident in the presence of a potent inflammatory trigger.…”

Constructing a competing endogenous RNA network for osteoarthritis

“…Another study showed that DUSP1 may act as the protector of OA fibroblast-like synoviocytes in OA patients by inhibiting the MAPK signaling pathway (21). Interestingly, Pest et al showed that the deletion of DUSP1 did not increase the incidence of OA in mice (22). Thus, DUSP1 may have different biological functions in different conditions.…”