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

The Journal of Clinical Investigation
Corine MartineauRené St-Arnaud

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.

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Citations

Oct 12, 2018·British Journal of Clinical Pharmacology·Glenville Jones, Martin Kaufmann
Oct 16, 2018·Endocrine Reviews·Roger BouillonJohn Bilezikian
Oct 8, 2019·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Roger Bouillon, Dan Bikle
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Datasets Mentioned

BETA
GSE112449
AK009853

Methods Mentioned

BETA
targeted mutation
Knockout
PCR
dissection
enzymatic assay

Software Mentioned

ImageJ
GraphPad Prism
GraphPad
InstaRecon
CTAn
Basic Local Alignment Search Tool ( BLAST )

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