Session Title: Biology and Pathology of Bone and Joint - Poster I
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Degenerative Disc Disease (DDD), one of the main causes of low back pain, is characterized by degeneration of intervertebral disc, nucleus pulposus (NP), and cartilage matrix, resulting in decreased disc height and function. Treatment of DDD is limited to analgesics or surgery aimed at relieving symptoms, and no current therapy can reverse disc degeneration. Wnt signaling plays an important role in DDD by regulating the proliferation and differentiation of resident NP cells. SM04690, a novel, small-molecule, Wnt pathway inhibitor was evaluated in a series of preclinical studies to determine its potential to induce proliferation and differentiation of primary NP cells, thereby promoting disc healing.
Methods: Wnt pathway inhibition was measured using a cell-based reporter assay. In vitro proliferation of NP cells from rat coccygeal discs, treated with vehicle or various concentrations of SM04690 for 5 days was measured by cell doubling index (CDI= cell number/initial cell number/days). Differentiation of NP cells into “chondrocyte-like” NP cells with vehicle or SM04690 treatment for 12 days was measured by Alcian blue staining and absorbance based quantification. Pharmacokinetics were evaluated by intradiscal injection in rats and rabbits, followed by analysis of compound concentrations in the disc and plasma. In vivo efficacy was evaluated in a rat coccygeal intervertebral disc “needle puncture” model using radiographic measurement of disk height index (DHI = disk height/vertebral height), and histological scoring (total 4-16) of Safranin O-stained sections for integrity of annulus fibrosus (AF), border between AF and NP, cellularity, and matrix of NP.
Results: SM04690 demonstrated potent (EC50 =11nM) and selective inhibition of Wnt signaling. In vitro proliferation measured as CDI was ~2-fold higher in cells treated with SM04690 compared to vehicle (P<0.05). Cells treated with SM4690 also showed significantly increased Alcian blue absorbance, indicating differentiation to “chondrocyte-like” cells (P<0.01). Single intradiscal injection of SM04690 resulted in disc concentrations >EC50 for >180 days, with minimal systemic exposure or toxicity, measured as behavioral, health, gross morphology, and microscopic adverse changes. In the rat DDD model, SM04690 treatment increased Safranin O-stained cartilage matrix (Figure A), thereby resulting in significantly increased radiographically measured % DHI (P<0.05; Figure B), and decreased histology scores (P<0.05; Figure C) vs. vehicle control.
Conclusion: SM04690, a small molecule Wnt pathway inhibitor promoted proliferation and differentiation of NP cells in vitro. In a rat model of DDD, SM04690 regenerated NP cells and cartilage matrix, and improved disc height, health, and shape compared to vehicle, with minimal plasma exposure or systemic toxicity. These results suggested that SM04690 has potential as a treatment for DDD.
To cite this abstract in AMA style:Barroga C, Deshmukh V, Dellamary L, Stewart J, Hu H, Hood J, Yazici Y. Discovery of a Small Molecule Inhibitor of the Wnt Pathway (SM04690) As a Potential Treatment for Degenerative Disc Disease [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/discovery-of-a-small-molecule-inhibitor-of-the-wnt-pathway-sm04690-as-a-potential-treatment-for-degenerative-disc-disease/. Accessed May 24, 2019.
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