Background/Purpose: The absence of effective disease-modifying drugs remains an important unmet need in the treatment of osteoarthritis. In recent years, novel pharmacological treatments including targeting TGF-beta signaling in subchondral bone (Zhen et al., Nat Med 2013) or senescence of joint tissues (Jeon et al., Nat Med 2017) have demonstrated promising efficacy in experimental osteoarthritis. However, the translation from experimental models to humans has not been pursued to date. Here, we determined therapeutic and deleterious side effects of these treatment strategies in a preclinical explant model of human knee and facet joint osteoarthritis.

Methods: Osteochondral tissue explants of osteoarthritic human knee tibial plateaus (n=10) or lumbar facet joints (n=10) were cultured for one week in the presence and absence of an inflammatory stimulus (1 μg/mL LPS). Specimens were left untreated (control) or treated with a senolytic agent (4.5 mg/mL quercetin) or inhibitor of TGF-beta receptor signaling (10μm SB-505124). Subchondral bone turnover (Pro-Collagen-Iα) and tissue inflammation (IL-6, MCP-1) was assessed by ELISA. Tissue viability was determined by MTT staining. Data was analyzed by one-way ANOVA.

Results: Explanted tissues showed no appreciable loss of viability during culture and drug treatment. LPS challenge led to a 4- and 3-fold induction of IL-6 and MCP-1 tissue secretion, respectively. Subchondral bone turnover was not affected by inflammatory conditions. The therapeutic effect of TGF-beta signaling inhibition was revealed by a drastic reduction of pro-Col-I (~75%) and IL-6 (~50%) secretion. Unexpectedly, MCP-1 secretion was significantly elevated (~200%) revealing a TGF-beta-dependent negative feedback mechanism. This side effect was specific for knee osteoarthritis and not observed in facet joint specimens. Senolytic treatment with quercetin did not affect bone turnover, yet strongly induced IL-6 tissue secretion under control (~400%) and inflammatory conditions (~200%).

Conclusion: Taking advantage of a preclinical model of human osteoarthritis, we established therapeutic efficacy of TGF-beta signaling inhibition on subchondral bone turnover in knee and spine. Elevated MCP-1 secretion upon TGF-beta targeting and increased tissue inflammation using senolytic drugs prompt careful evaluation of these potential disease-modifying agents transitioning from experimental to human osteoarthritis. Osteochondral explant models are highly valuable for determining joint-specific tissue responses.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preclinical-evaluation-of-targeting-tgf-beta-signaling-and-senescence-in-ex-vivo-models-of-human-knee-and-spine-osteoarthritis/