The Role of GDF5 in Regulating Enthesopathy Development in the Hyp Mouse Model of XLH

Authors

Melissa Sorsby
Shaza Almardini
Ahmad Alayyat
Ashleigh Hughes
Shreya Venkat
Mansoor Rahman
Jiana Baker
Rakshya Rana
Vicki Rosen
Eva S Liu

Language

English

Publication Date

8-21-2024

Journal

Journal of Bone and Mineral Research

DOI

10.1093/jbmr/zjae086

PMID

38836497

PMCID

PMC11337578

PubMedCentral® Posted Date

6-5-2024

PubMedCentral® Full Text Version

Post-print

Abstract

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX, leading to rickets and osteomalacia. Adults affected with XLH develop a mineralization of the bone-tendon attachment site (enthesis), called enthesopathy, which causes significant pain and impaired movement. Entheses in mice with XLH (Hyp) have enhanced bone morphogenetic protein (BMP) and Indian hedgehog (IHH) signaling. Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses. It was previously shown that mRNA expression of growth/differentiation factor 5 (Gdf5) is enhanced in Hyp entheses at P14. Thus, to determine a role for GDF5 in enthesopathy development, Gdf5 was deleted globally in Hyp mice and conditionally in Scx + cells of Hyp mice. In both murine models, BMP/IHH signaling was similarly decreased in Hyp entheses, leading to decreased enthesopathy. BMP/IHH signaling remained unaffected in WT entheses with decreased Gdf5 expression. Moreover, deletion of Gdf5 in Hyp entheses starting at P30, after enthesopathy has developed, partially reversed enthesopathy. Taken together, these results demonstrate that while GDF5 is not essential for modulating BMP/IHH signaling in WT entheses, inappropriate GDF5 activity in Scx + cells contributes to XLH enthesopathy development. As such, inhibition of GDF5 signaling may be beneficial for the treatment of XLH enthesopathy.

Keywords

Animals, Mice, Bone Morphogenetic Proteins, Disease Models, Animal, Enthesopathy, Familial Hypophosphatemic Rickets, Growth Differentiation Factor 5, Signal Transduction, preclinical studies, genetic mouse models, BMPs, osteomalacia and rickets, molecular pathways- development

Published Open-Access

yes

Recommended Citation

Sorsby, Melissa; Almardini, Shaza; Alayyat, Ahmad; et al., "The Role of GDF5 in Regulating Enthesopathy Development in the Hyp Mouse Model of XLH" (2024). Staff and Researcher Publications. 3.
https://digitalcommons.library.tmc.edu/clinic_pub/3