Palovarotene reduces heterotopic ossification in juvenile FOP mice but exhibits pronounced skeletal toxicity.

ELife
John B Lees-ShepardDavid J Goldhamer

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs' skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.

References

Dec 1, 1992·Journal of the American Academy of Dermatology·A Vahlquist
Oct 1, 1987·Archives of Biochemistry and Biophysics·M A Campbell, C J Handley
Jan 1, 1970·Journal of Comparative Pathology·R J GartnerA A Seawright
Feb 1, 1993·The Journal of Bone and Joint Surgery. American Volume·F S KaplanM A Zasloff
Dec 30, 1999·Endocrinology·F De LucaJ Baron
Feb 13, 2001·Developmental Biology·Y Y KisanukiM Yanagisawa
Oct 19, 2001·Journal of the American Academy of Dermatology·J J DiGiovanna
Mar 12, 2004·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Cory J XianBruce K Foster
Oct 31, 2007·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Paul C BillingsFrederick S Kaplan
Feb 5, 2008·The Journal of Bone and Joint Surgery. American Volume·Gregory K DeirmengianFrederick S Kaplan
May 10, 2008·The Journal of Comparative Neurology·Karin RoeschConstance L Cepko
Jan 24, 2009·Genesis : the Journal of Genetics and Development·Masakazu YamamotoDavid J Goldhamer
Jan 19, 2010·Nature Cell Biology·Aaron W B JoeFabio M V Rossi
Sep 17, 2010·The Journal of Biological Chemistry·Julie A WilliamsMasahiro Iwamoto
Oct 20, 2010·Proceedings of the National Academy of Sciences of the United States of America·Nengyin ShengNaihe Jing
Aug 10, 2011·Journal of Experimental Zoology. Part B, Molecular and Developmental Evolution·Hyuk-Jae KwonHan-Sung Jung
Nov 3, 2011·Journal of Cell Science·Akiyoshi UezumiSo-ichiro Fukada
Feb 7, 2012·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Michael N WosczynaDavid J Goldhamer
Apr 18, 2012·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Salin A ChakkalakalEileen M Shore
Sep 4, 2015·Science Translational Medicine·Sarah J HatsellAris N Economides
Dec 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Kyosuke HinoJunya Toguchida
Feb 21, 2016·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Salin A ChakkalakalEileen M Shore
Mar 31, 2016·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Robert J PignoloFrederick S Kaplan
Apr 9, 2016·Journal of Basic and Clinical Pharmacy·Anroop B Nair, Shery Jacob
Jun 23, 2016·Cold Spring Harbor Perspectives in Biology·Maria Namwanje, Chester W Brown
Aug 6, 2016·Methods in Molecular Biology·Arpita A Biswas, David J Goldhamer
Nov 25, 2016·Science Translational Medicine·Devaveena DeyPaul B Yu
Aug 8, 2017·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Jaymin UpadhyaySarah J Hatsell
Sep 30, 2017·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Benjamin M WheatleyThomas A Davis
Nov 4, 2017·Bone·Julia HauptEileen M Shore

❮ Previous
Next ❯

Citations

Nov 14, 2019·Current Osteoporosis Reports·Koji MatsuoEdward C Hsiao
Apr 17, 2020·International Journal of Molecular Sciences·Sonia A GarciaMotomi Enomoto-Iwamoto
Mar 19, 2019·Intractable & Rare Diseases Research·Durval Batista PalharesAlmir Sousa Martins
Sep 30, 2020·Disease Models & Mechanisms·Arun-Kumar Kaliya-PerumalPhilip W Ingham
Sep 6, 2020·Biomedicines·Hiroshi Kitoh
Mar 7, 2021·Biomedicines·Francesc VenturaGonzalo Sanchez-Duffhues
Apr 12, 2021·Current Opinion in Pharmacology·Emily Parker, Mark W Hamrick
Jun 25, 2021·Science Translational Medicine·Qian CongYingzi Yang

❮ Previous
Next ❯

Methods Mentioned

BETA
bioluminescence imaging
PCR
genotyping
dissection
FACS

Software Mentioned

Spot Advanced
Photoshop
eLife
GraphPad Prism
3D Slicer
Living Image
SoftMouse Colony Management

Related Concepts

Related Feeds

Adenomatous Polyposis Coli

Adenomatous polyposis coli is a protein encoded by the APC gene and acts as a tumor suppressor. Discover the latest research on adenomatous polyposis coli here.

Adult Stem Cells

Adult stem cells reside in unique niches that provide vital cues for their survival, self-renewal, and differentiation. They hold great promise for use in tissue repair and regeneration as a novel therapeutic strategies. Here is the latest research.

Related Papers

Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Salin A ChakkalakalEileen M Shore
Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research
Frederick S Kaplan, R M Smith
© 2022 Meta ULC. All rights reserved