Session Title: Biology and Pathology of Bone and Joint - Poster II
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Chronic tendinopathy is an inflammatory and degenerative condition caused by injuries or overuse. Current therapeutic options focus on alleviating the symptoms and pain rather than treatment of the underlying causes. The Wnt pathway plays an important role in tenocyte differentiation, and is upregulated in chronic tendinopathy. SM04755, a novel, topical, small-molecule Wnt pathway inhibitor, was evaluated in preclinical studies to determine its potential to inhibit inflammation, reduce fibrosis and increase tenocyte differentiation, thereby promoting tendon healing.
Methods: Wnt pathway inhibition was measured via cell-based reporter assay. Anti-inflammatory activity was evaluated by measuring TNFα and IL-6 secretion using ELISA in lipopolysaccharides (LPS)-stimulated THP-1 monocytes and anti-CD3/anti-CD28-stimulated peripheral blood mononuclear cells (PBMCs). Histological expression of scleraxis A (SCXA), tenomodulin and tenascin C were measured using high-content imaging to evaluate differentiation of human mesenchymal stem cells (hMSCs) to tenocytes. Pharmacokinetics were evaluated by topical application in rats, dogs and mini-pigs, followed by analysis of compound concentrations in tendon and plasma. In vivo efficacy of topical SM04755 was evaluated in an intra-tendon collagenase-induced rodent tendinopathy model by scoring (range 5-20) several histological indicators of tendon health. Inflammation in the rodent model was measured by chemokine ligand 1 (CXCL1) levels in plasma by ELISA and other inflammatory markers in the tendon by qPCR. Tendon regeneration was evaluated by qPCR based gene expression of tenocyte differentiation markers- SCXA and tenascin C.
Results: SM04755 demonstrated potent (EC50=152nM) and selective inhibition of Wnt signaling. SM04755 inhibited both LPS and anti-CD3/anti-CD28 induced TNFα and IL6 secretion (EC50=500nM) in THP-1 cells and PBMCs. SM04755 induced differentiation of hMSCs into SCXA, tenomodulin, and tenascin C expressing tenocytes (EC50=200nM). A single topical application of SM04755 resulted in tendon concentrations >EC50 for up to 24hrs, with minimal systemic drug exposure or toxicity. In the collagenase-induced model, SM04755 treatment significantly increased the mean tendon health score (p<0.01, n=6), decreased the plasma levels of CXCL1 (p<0.05), reduced gene expression of pro-inflammatory markers (IL-6, TNF-a, IL-1b, INF-g, IL-8) (p<0.05), and increased expression of SCXA and tenascin C in tendon compared to vehicle.
Conclusion: Topical SM04755 reduced tendon inflammation and an inflammatory marker in plasma, showed evidence of tendon regeneration, and increased tendon health scores compared to vehicle in a rodent tendinopathy model. Plasma exposure and systemic toxicity were minimal. SM04755 demonstrates potential to promote tendon healing in chronic tendinopathy.
To cite this abstract in AMA style:Deshmukh V, Seo T, Ibanez M, Dellamary L, Stewart J, Hood J, Yazici Y. Discovery of a Small Molecule Inhibitor of the Wnt Pathway (SM04755) As a Potential Topical Treatment for Chronic Tendinopathy [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/discovery-of-a-small-molecule-inhibitor-of-the-wnt-pathway-sm04755-as-a-potential-topical-treatment-for-chronic-tendinopathy/. Accessed November 15, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/discovery-of-a-small-molecule-inhibitor-of-the-wnt-pathway-sm04755-as-a-potential-topical-treatment-for-chronic-tendinopathy/