Understanding the Role of Sclerostin in Post-Traumatic Osteoarthritis Development in Mice

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.

Year	Entry
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Year

Entry

2005

Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma H-L, Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature. March 31, 2005;434(7033):644-648.

2005

Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, Harris SE, Wu D. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. May 20, 2005;280(20):19883-19887.

2002

Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor–related protein 5. NEJM. May 16, 2002;346(20):1513-1521.

2008

Li X, Ominsky MS, Niu Q, Sun N, Daugherty B, D'Agostin D, Kurahara C, Gao Y, Cao J, Gong J, Asuncion F, Barrero M, Warmington K, Dwyer D, Stolina M, Morony S, Sarosi I, Kostenuik PJ, Lacey DL, Simonet WS, Ke HZ, Paszty C. Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res. June 2008;23(6):860-869.

2010

Glasson SS, Chambers MG, Van Den Berg WB, Little CB. The OARSI histopathology initiative: recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage. October 2010;18(suppl 3):S17-S23.