Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
JAK2-IGF1 axis in osteoclasts regulates postnatal growth in mice
David W. Dodington, … , Wendy E. Ward, Minna Woo
David W. Dodington, … , Wendy E. Ward, Minna Woo
Published March 8, 2021
Citation Information: JCI Insight. 2021;6(5):e137045. https://doi.org/10.1172/jci.insight.137045.
View: Text | PDF
Research Article Bone biology Endocrinology

JAK2-IGF1 axis in osteoclasts regulates postnatal growth in mice

  • Text
  • PDF
Abstract

Osteoclasts are specialized cells of the hematopoietic lineage that are responsible for bone resorption and play a critical role in musculoskeletal disease. JAK2 is a key mediator of cytokine and growth factor signaling; however, its role in osteoclasts in vivo has yet to be investigated. To elucidate the role of JAK2 in osteoclasts, we generated an osteoclast-specific JAK2–KO (Oc-JAK2–KO) mouse using the Cre/Lox-P system. Oc-JAK2–KO mice demonstrated marked postnatal growth restriction; however, this was not associated with significant changes in bone density, microarchitecture, or strength, indicating that the observed phenotype was not due to alterations in canonical osteoclast function. Interestingly, Oc-JAK2–KO mice had reduced osteoclast-specific expression of IGF1, suggesting a role for osteoclast-derived IGF1 in determination of body size. To directly assess the role of osteoclast-derived IGF1, we generated an osteoclast-specific IGF1–KO mouse, which showed a similar growth-restricted phenotype. Lastly, overexpression of circulating IGF1 by human transgene rescued the growth defects in Oc-JAK2–KO mice, in keeping with a causal role of IGF1 in these models. Together, our data show a potentially novel role for Oc-JAK2 and IGF1 in the determination of body size, which is independent of osteoclast resorptive function.

Authors

David W. Dodington, Jenalyn L. Yumol, Jiaqi Yang, Evan Pollock-Tahiri, Tharini Sivasubramaniyam, Sandra M. Sacco, Stephanie A. Schroer, Yujin E. Li, Helen Le, Wendy E. Ward, Minna Woo

×

Figure 1

Generation of osteoclast-specific JAK2–KO mice.

Options: View larger image (or click on image) Download as PowerPoint
Generation of osteoclast-specific JAK2–KO mice.
Ctsk-Cre–expressing mice...
Ctsk-Cre–expressing mice were bred to mTmG mice or mice with floxed Jak2 gene to generate reporter and osteoclast-specific JAK2–KO mice. (A) Representative images of knee joint from mTmG+ (n = 3) and Ctsk-Cre+mTmG+ mice (n = 3) at 1 week of age stained for H&E, tartrate resistant alkaline phosphatase (TRAP), and imaged for fluorescence of endogenous Cre reporter activity. Staining/imaging was performed on adjacent serial frozen sections. Scale bars: 100 μm. (B) Representative fluorescence images of cartilage (femur growth plate), brain, hypothalamus, testis, ovary, pancreas, liver/gallbladder, small intestine, kidney, and thyroid from Ctsk-Cre+mTmG+ mice (n = 3). Tissues were collected from 8-week-old mice, except for growth plates, which were collected from 1-week-old mice. Scale bars: 100 μm. (C) Jak2 mRNA expression in bone [n = 7 (control), n = 4 (Ctsk-Cre+Jak2fl/fl)], BM-derived osteoclasts [n = 3 (control), n = 3 (Ctsk-Cre+Jak2fl/fl)], BM-derived macrophages [n = 3 (control), n = 3 (Ctsk-Cre+Jak2fl/fl)], liver [n = 4 (control), n = 3 (Ctsk-Cre+Jak2fl/fl)], testis [n = 4 (control), n = 3 (Ctsk-Cre+Jak2fl/fl)], ovary [n = 4 (control), n = 4 (Ctsk-Cre+Jak2fl/fl)], and hypothalamus [n = 4 (control), n = 3 (Ctsk-Cre+Jak2fl/fl)] from control and Ctsk-Cre+Jak2fl/fl mice. Values are normalized to 18S mRNA levels and presented as fold change over control group. (D) Representative images of femur from control (n = 3) and Ctsk-Cre+Jak2fl/fl mice (n = 3) stained for TRAP and immunostained for JAK2. Staining was performed on adjacent serial sections. The circle highlights TRAP+ multinucleated giant cells. Scale bars: 10 μm. Data represent mean ± SEM. Differences between groups were analyzed for statistical significance by Student’s unpaired t test; *P < 0.05. Oval highlights TRAP+ multinucleated giant cells.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts