Upwards of 10% of all bone fractures fail to heal properly, with dysfunctional repair even more common in individuals with metabolic defects. Vitamin D has been implicated in fracture healing, which involves formation of a soft callus at the fracture site that is later mineralized and ossified. In this episode, René St-Arnaud and colleagues determined that that ossification is impaired in Cyp24a1-deficient mice, which are unable to synthesize the vitamin D metabolite 24R,25-dihydroxyvitamin D3, following traumatic bone injury. FAM57B2 was upregulated in the fracture callus of Cyp24a1-deficient mice and an interaction between FAM57B2 and 24R,25-dihydroxyvitamin D3 in chondrocytes produced lactosylceramide, which supports callus mineralization. Importantly, lactosylceramide supplementation improved mineralization in both Cyp24a1- and Fam57b2-deficient calluses, suggesting that this 24R,25-dihydroxyvitamin D3–dependent pathway has potential to be targeted to optimize bone repair after fracture.
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.
Corine Martineau, Roy Pascal Naja, Abdallah Husseini, Bachar Hamade, Martin Kaufmann, Omar Akhouayri, Alice Arabian, Glenville Jones, René St-Arnaud