Introduction: Lifestyle-impacting osteoarthritis (OA) is highly prevalent in animals, yet disease-modifying
treatments remain elusive. Chondrogenic effects of rFGF18 are encouraging; however,
therapeutic application is limited by the frequency of intra-articular re-administration
required to overcome joint pharmacokinetics. We evaluated the effects of a single
AAV2-FGF18 injection on chondrocyte proliferation, gene expression, and cartilage
thickness.
Materials and Methods: Cytocompatibility and transduction efficiency was assessed in primary chondrocytes
and synoviocytes. Gene expression was analyzed by RNA-seq on chondrocytes subjected
to AAV2-FGF18, AAV2-GFP, rFGF18 protein, and PBS. Durability of gene expression was
confirmed by in vivo bioluminescence imaging. Cartilage anabolism was evaluated by
measuring thickness of tibial and anterior medial meniscal cartilage in male Sprague-Dawley
rats (300–375 g).
Results: Transduction efficiency reached 58 ± 16% in synoviocytes and 97 ± 3% in chondrocytes
(MOI 50k) after 168 hours in culture, with no decreases in cell viability. HEK- and
E. coli-expressed rFGF18 induced dose-dependent chondrocyte proliferation at 1 to 10k ng/mL;
AAV2-FGF18 induced similar increases at 100 to 1,000 MOI. rFGF18 protein analog and
AAV2-FGF18 both upregulated hyaline cartilage-associated genes (HAS2, COL2A1), while
downregulating fibrocartilage-associated COL1A1 (RNA-seq). This translated to weight-normalized
cartilage thickness increases on the tibial plateau and meniscal tip.
Discussion/Conclusion: AAV2-FGF18 shows promise for the restoration of articular cartilage by promoting
hyaline cartilage-related gene expression, increasing anatomically relevant ECM production,
and inducing chondrocyte proliferation.
Acknowledgments: Funding for this work was provided by Remedium.
