Preclinical safety and efficacy of 24R,25-dihydroxyvitamin D3 or lactosylceramide treatment to enhance fracture repair

Corine Martineau; Martin Kaufmann; Alice Arabian; Glenville Jones; René St-Arnaud

Journal of Orthopaedic Translation (Jul 2020)

Preclinical safety and efficacy of 24R,25-dihydroxyvitamin D3 or lactosylceramide treatment to enhance fracture repair

Corine Martineau,
Martin Kaufmann,
Alice Arabian,
Glenville Jones,
René St-Arnaud

Affiliations

Corine Martineau: Research Centre, Shriners Hospitals for Children – Canada, Montreal, Quebec, H4A 0A9, Canada
Martin Kaufmann: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada; Department of Surgery, Queen's University, Kingston, Ontario, K7L 3N6, Canada
Alice Arabian: Research Centre, Shriners Hospitals for Children – Canada, Montreal, Quebec, H4A 0A9, Canada
Glenville Jones: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, K7L 3N6, Canada
René St-Arnaud: Research Centre, Shriners Hospitals for Children – Canada, Montreal, Quebec, H4A 0A9, Canada; Department of Human Genetics, McGill University, Montreal, Quebec, H3A 1A1, Canada; Department of Surgery, McGill University, Montreal, Quebec, H3A 1A1, Canada; Department of Medicine, McGill University, Montreal, Quebec, H3A 1A1, Canada; Research Institute of the McGill University Health Centre, Montreal, Quebec, H3H 2R9, Canada; Corresponding author. Research Centre, Shriners Hospitals for Children – Canada, 1003 Decarie Boulevard, Montreal, Quebec, H4A 0A9, Canada.

Journal volume & issue: Vol. 23
pp. 77 – 88

Abstract

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Background/Objective: Cyp24a1-null mice deficient in 24,25(OH)2D3 display impaired callus formation during the endochondral phase of bone fracture repair. The 24,25(OH)2D3 metabolite acted by binding to the TLC domain containing 3B isoform 2 (TLCD3B2, previously named FAM57B2) effector protein, which then synthesizes lactosylceramide (LacCer). Treatment with 24,25(OH)2D3 or LacCer restored callus size and mechanical properties in Cyp24a1-null mice. Methods: To assess the safety of these molecules and test their efficacy for bone healing in wild-type, non-genetically modified mice, we treated 12-week-old, osteotomized C57BL/6 female mice with each compound for up to 21 days post-osteotomy. Control cohorts were injected with vehicle. Results: Neither compound was found to exhibit any nephro- nor hepato-toxicity. Calcemia remained stable throughout the experiment and was unaffected by either treatment. Supplementation with 24,25(OH)2D3 increased circulating levels of this metabolite about 8-fold, decreased 1,25(OH)2D3 levels, and significantly increased circulating 1,24,25(OH)3D3 levels, suggesting 1?-hydroxylation of 24,25(OH)2D3. TLCD3B2 was found to be expressed in fracture callus at the surface of unmineralized or pre-mineralized cartilage on day 10 and day 12 post-osteotomy and to progressively recede to become undetectable by day 18. Treatment with 24,25(OH)2D3 or LacCer reduced the number of TLCD3B2-positive cells. Both treatments also significantly increased stiffness and elastic modulus of the healing bone callus. Conclusion: Exogenous administration of 24,25(OH)2D3 or LacCer improved the biomechanical properties of repaired bones in wild-type animals without affecting circulating calcium levels or other blood parameters, demonstrating preclinical safety and efficacy. Translational potential: Our data suggest the use of 24R,25-dihydroxyvitamin D3 or lactosylceramide for ameliorating fracture healing in clinical practice.

Published in Journal of Orthopaedic Translation

ISSN: 2214-031X (Print); 2214-0328 (Online)
Publisher: Elsevier
Country of publisher: Hong Kong
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the musculoskeletal system
Website: http://www.journals.elsevier.com/journal-of-orthopaedic-translation/

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