Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2
Corine Martineau, … , Glenville Jones, René St-Arnaud
Corine Martineau, … , Glenville Jones, René St-Arnaud
Published July 16, 2018
Citation Information: J Clin Invest. 2018;128(8):3546-3557. https://doi.org/10.1172/JCI98093.
View: Text | PDF
Research Article Bone biology Endocrinology

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

  • Text
  • PDF
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.

Authors

Corine Martineau, Roy Pascal Naja, Abdallah Husseini, Bachar Hamade, Martin Kaufmann, Omar Akhouayri, Alice Arabian, Glenville Jones, René St-Arnaud

×

Figure 3

FAM57B2 functional characterization.

Options: View larger image (or click on image) Download as PowerPoint
FAM57B2 functional characterization.
(A and B) Ceramide synthase assay. ...
(A and B) Ceramide synthase assay. Lysates from HEK293 cells transfected with Fam57b2 or empty vector (A) were used in enzyme assays. Products were separated by TLC as described in Methods. Arrows indicate lipid standards. Results are representative of 3 independent experiments. 25D, 25(OH)D3; 24R25D, 24R,25(OH)2D3; 24S25D, 24S,25(OH)2D3; 1,25D, 1,25(OH)2D3; 1,24,25D, 1,24,25(OH)3D3; M, lipid markers: PE, LacCer, PC, and Sp. (C–F) Static morphometry in control (fl/fl WT) and chondrocyte-specific mutant (fl/fl Cre) Fam57b-floxed mice. Bone length (C) and trabecular bone volume (D), number (E), and thickness (F) were assessed by micro-CT. P > 0.05, by 2-tailed t test for C–F. (G) Bone stiffness was calculated from the 3PBT. P > 0.05, by 2-tailed t test. (H) Fam57b2 expression in day-18 fracture callus from control or Cyp24a1–/– mice supplemented or not with 50 μg/kg daily C18-LacCer. *P < 0.05, by 2-way ANOVA followed by Bonferroni’s post test. (I) Fam57b2 expression in primary chondrocytes from control or Cyp24a1–/– mice, with or without a 24-hour exposure to 1 μM LacCer. **P < 0.01 and ***P < 0.001, by 2-way ANOVA followed by Bonferroni’s post test (n = 6). (J) Callus volume quantification was determined by micro-CT. *P < 0.05 and **P < 0.01, by 2-way ANOVA followed by Bonferroni’s post test. (K) X-ray projections of callus of chondrocyte-specific Fam57b-deficient mice on day 14 and day 18 after osteotomy. fl/fl WT, control Fam57b mice; fl/fl Cre, chondrocyte-specific Fam57b-deficient mice. The number of animals per group is indicated in parentheses.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts