Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2

  • J Clin Invest. 2018 Aug 1;128(8):3546-3557. doi: 10.1172/JCI98093.
Corine Martineau  1 ,  Roy Pascal Naja  1  2 ,  Abdallah Husseini  1  3 ,  Bachar Hamade  1  3 ,  Martin Kaufmann  4 ,  Omar Akhouayri  1 ,  Alice Arabian  1 ,  Glenville Jones  4 ,  René St-Arnaud  1  2  3  5  6
Affiliations
  • 1. Research Centre, Shriners Hospitals for Children - Canada, Montreal, Quebec, Canada.
  • 2. Department of Human Genetics, and.
  • 3. Department of Surgery, McGill University, Montreal, Quebec, Canada.
  • 4. Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • 5. Department of Medicine, McGill University, Montreal, Quebec, Canada.
  • 6. Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
PMID: 30010626 DOI: 10.1172/JCI98093
Abstract

The biological activity of 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] remains controversial, but it has been suggested that it contributes to fracture healing. Cyp24a1-/- mice, synthesizing no 24R,25(OH)2D3, show suboptimal endochondral ossification during fracture repair, with smaller callus and reduced stiffness. These defects were corrected by 24R,25(OH)2D3 treatment, but not by 1,25-dihydroxyvitamin D3. Microarrays with Cyp24a1-/- callus mRNA identified FAM57B2 as a mediator of the 24R,25(OH)2D3 effect. FAM57B2 produced lactosylceramide (LacCer) upon specific binding of 24R,25(OH)2D3. Fam57b inactivation in chondrocytes (Col2-Cre Fam57bfl/fl) phenocopied the callus formation defect of Cyp24a1-/- mice. LacCer or 24R,25(OH)2D3 injections restored callus volume, stiffness, and mineralized cartilage area in Cyp24a1-null mice, but only LacCer rescued Col2-Cre Fam57bfl/fl mice. Gene expression in callus tissue suggested that the 24R,25(OH)2D3/FAM57B2 cascade affects cartilage maturation. We describe a previously unrecognized pathway influencing endochondral ossification during bone repair through LacCer production upon binding of 24R,25(OH)2D3 to FAM57B2. Our results identify potential new approaches to ameliorate fracture healing.

Keywords
Bone Biology; Endocrinology; Orthopedics.
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