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Systemic treatment with the sphingosine-1-phosphate analog FTY720 does not improve fracture healing in mice
Aline Heilmann1, Thorsten Schinke, Ronny Bindl
1Institute of Orthopaedic Research and Biomechanics, Center of Musculoskeletal Research, University of Ulm, Ulm, Germany.
Abstract:
Sphingosine-1-phosphate (S1P) has recently been recognized as a crucial coupling molecule of osteoclast and osteoblast activity provoking osteoanabolic effects. Targeting S1P receptors could, therefore, be a potential strategy to support bone formation in osteopenic diseases or in fracture repair. Here we investigated whether systemic treatment with the S1P analog FTY720 (Fingolimod) could improve fracture healing. Twelve-week-old, female C57BL/6 mice received an osteotomy of the femur, which was stabilized using an external fixator. The mice received a daily subcutaneous injection of either FTY720 (6 mg/kg) or vehicle from the third postoperative day. Fracture healing was evaluated after 10 and 21 days using biomechanical testing, µ-computed tomography, and histomorphometry. Because FTY720 is supposed to influence osteoclast recruitment, osteoclasts were identified in the fracture callus by staining for tartrate resistant acid phosphatase (TRAP). There were no significant differences in callus mechanical properties, tissue composition and osteoclast number between the groups, suggesting that systemically applied FTY720 did not influence bone regeneration in this model of regular fracture healing. Even if further studies should test the potency of FTY720 under unfavorable healing conditions, we conclude that the effect of systemically applied FTY720 on fracture healing might be inferior compared to other anabolic treatments. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1845-1850, 2013.
Insights
Systemic treatment with FTY720 (Fingolimod) did not improve fracture healing in mice. This sphingosine-1-phosphate analog showed no significant anabolic effects on bone regeneration in this study.
Area of Science:
- Orthopaedic Research
- Bone Biology
- Pharmacology
Background:
- Sphingosine-1-phosphate (S1P) is a key regulator of osteoclast and osteoblast activity, suggesting potential for S1P receptor targeting in bone diseases.
- FTY720 (Fingolimod) is an S1P analog with potential osteoanabolic effects, making it a candidate for enhancing bone formation.
Purpose of the Study:
- To investigate the efficacy of systemic FTY720 (Fingolimod) treatment in improving fracture healing.
- To evaluate the impact of FTY720 on bone regeneration and osteoclast activity in a mouse femur fracture model.
Main Methods:
- Female C57BL/6 mice underwent femur osteotomy stabilized with an external fixator.
- Daily subcutaneous injections of FTY720 (6 mg/kg) or vehicle were administered post-operation.
- Fracture healing was assessed at 10 and 21 days using biomechanical testing, micro-computed tomography, and histomorphometry, including TRAP staining for osteoclasts.
Main Results:
- No significant differences were observed in callus mechanical properties between FTY720-treated and vehicle-treated groups.
- Histomorphometry and micro-CT analysis revealed no significant differences in tissue composition or osteoclast numbers.
- Systemic FTY720 administration did not demonstrably influence bone regeneration in this regular fracture healing model.
Conclusions:
- Systemic application of FTY720 did not enhance fracture healing in the studied mouse model.
- The anabolic effects of FTY720 on bone regeneration appear limited in regular fracture healing.
- Further research is warranted to explore FTY720's potential under compromised healing conditions, but its efficacy may be inferior to other anabolic treatments.
