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. Epub 2018 Jul 16.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cartilage / metabolism*
  • Cartilage / pathology
  • Chondrocytes / metabolism*
  • Chondrocytes / pathology
  • Fracture Healing*
  • Fractures, Bone / genetics
  • Fractures, Bone / metabolism*
  • Fractures, Bone / pathology
  • Fractures, Bone / therapy
  • Mice
  • Mice, Knockout
  • Osteogenesis*
  • Vitamin D / analogs & derivatives*
  • Vitamin D / metabolism
  • Vitamin D3 24-Hydroxylase / deficiency*


  • dihydroxy-vitamin D3
  • Vitamin D
  • Cyp24a1 protein, mouse
  • Vitamin D3 24-Hydroxylase