Osteoarthritis (OA), a joint inflammatory disease commonly described by the breakdown of articular cartilage, with major contributing factors including aging and traumatic injuries. To date, OA treatments are limited by surgical procedures and pain management; hence OA patients are anxiously awaiting the development of new pharmacologic interventions. Recent studies projected that the presence of Sclerostin (Sost) affecting Wnt signaling may modulate the metabolic processes in the articular chondrocyte. Therefore, the research conducted here is to explore whether Sost recombinant protein may be potentially used as a therapeutic to treat post-traumatic OA (PTOA) development, subsequent to trauma.
We examined the role of Sost in knee joints before and post non-invasive tibial compression (TC) OA injury in mice over expressing SOST (SOSTTG) and lacking Sost (SostKO) and comparing them to C57Bl/6 (WT) mouse strain as controls. We surveyed the effect in joint tissues by histological, micro-computed tomography, immunohistochemistry, and quantitative real-time PCR validation. After 16 weeks post TC injury, SOSTTG revealed an overall retention of the cartilage and reduces osteophyte formation comparing to SostKO and WTs. Interestingly, the overall activated matrix metalloproteinases (MMPs) are significantly reduces (~2 fold) in SOSTTG compared to SostKO and WT injured joints. After further validation, MMPs 2 (Gelatinase A) and 3 (Stromelysin-1) were dramatically down-regulated in SOSTTG injured joints. Consistent with the transgenic data, overall activated MMP levels were also reduced in WT injured joints after intra-articular administration of recombinant Sost protein shortly after the TC injury.
By taking a systems biology approach and investigating whole joint derived RNA by RNA Sequencing, we identified 1446 genes differentially regulated between injured and uninjured joints in WTs. The transcripts presented both know regulators and uninvestigated genes associated with OA. Moreover, we identified 18 long noncoding RNAs that are differentially expressed in the injured joints. This study provides the first global gene expression profile changes associated with PTOA development and progression in a TC model. Future pathways analysis, in strains of mice with varying PTOA phenotypic outcomes have the potential to unveil new prognostic biomarkers and therapeutic targets that may be further explored for the treatment of PTOA in humans.
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