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Effect of autotaxin inhibition in a surgically-induced mouse model of osteoarthritis
Poulami Datta1, Rajiv Gandhi1,2, Sayaka Nakamura1
1Arthritis Program, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
Objective:
Osteoarthritis (OA) is a degenerative joint disease with no approved disease modifying therapy. The enzyme autotaxin (ATX) converts lysophoshatidylcholine analogues to lysophosphatidic acid. Systemic inhibition of ATX reduces pain in animal models of OA; however, OA disease-modifying effects associated with ATX inhibition remain unknown. Here, we sought to determine whether local (knee joint) injection of an ATX inhibitor attenuates surgically-induced OA in mice.
Methods:
ATX expression was evaluated in human knee OA cartilage. Ten-week-old mice were subjected to surgically-induced OA. ATX inhibitor (PF-8380, 2.5ng/joint) was injected intra-articularly either at three and five weeks post-surgery or at two, four, six and eight weeks post-surgery and knee joints were evaluated by histopathology and immunohistochemistry to study the expression of catabolic and cell death markers. mRNA sequencing of human OA chondrocytes treated with/without ATX inhibitor was performed to identify differentially expressed transcripts, followed by pathway enrichment analysis.
Results:
ATX expression was elevated in severely degenerated cartilage compared to less degenerated human OA cartilage. In surgically-induced OA mice, intra-articular injection of ATX inhibitor at three and five weeks post-surgery partially protected knee joints from cartilage degeneration. Interestingly, earlier and more frequent ATX inhibitor injections did not confer significant protection. Immunohistochemical analysis showed decreased expression of catabolic and apoptotic markers with two ATX inhibitor injections. mRNA sequencing followed by pathway analysis identified pathways related to cholesterol analogue metabolism and cell-cycle that could be modulated by ATX inhibition in human OA chondrocytes.
Conclusion:
Local delivery of ATX inhibitor partially attenuates surgically-induced OA in mice.
Insights
Local injection of an autotaxin (ATX) inhibitor partially reduced knee joint degeneration in a mouse model of osteoarthritis (OA). This suggests ATX inhibition may offer a localized therapeutic strategy for OA.
Area of Science:
- Biochemistry
- Orthopedics
- Pharmacology
Background:
- Osteoarthritis (OA) is a degenerative joint disease lacking disease-modifying therapies.
- Autotaxin (ATX) is an enzyme involved in lysophosphatidic acid production; systemic ATX inhibition reduces OA pain in animal models.
- The disease-modifying effects of ATX inhibition in OA remain uncharacterized.
Purpose of the Study:
- To investigate the potential disease-modifying effects of local intra-articular autotaxin (ATX) inhibitor administration in a mouse model of surgically-induced osteoarthritis (OA).
Main Methods:
- Autotaxin (ATX) expression was assessed in human OA cartilage.
- Surgically-induced OA was created in mice, followed by intra-articular injections of an ATX inhibitor (PF-8380) at different time points.
- Knee joints were analyzed using histopathology, immunohistochemistry, and mRNA sequencing to evaluate OA progression, cell death, and gene expression changes.
Main Results:
- Elevated ATX expression was observed in degenerated human OA cartilage.
- Intra-articular ATX inhibitor injections at 3 and 5 weeks post-surgery partially protected mouse knee joints from cartilage degeneration.
- Reduced expression of catabolic and apoptotic markers was noted with two ATX inhibitor injections, while earlier/more frequent injections showed no significant additional benefit.
- mRNA sequencing identified pathways related to cholesterol metabolism and cell cycle modulated by ATX inhibition in human OA chondrocytes.
Conclusions:
- Local delivery of an autotaxin (ATX) inhibitor demonstrated partial attenuation of surgically-induced osteoarthritis in a mouse model.
- The findings suggest that localized ATX inhibition may represent a potential therapeutic strategy for modifying OA progression.
