Genetic and pharmacological inhibition of retinoic acid receptor γ function promotes endochondral bone formation

Kenta Uchibe, Jiyeon Son, Colleen Larmour, Maurizio Pacifici, Motomi Enomoto-Iwamoto, Masahiro Iwamoto

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The nuclear retinoic acid receptors (RARs) play key roles in skeletal development and endochondral ossification. Previously, we showed that RARγ regulates chondrogenesis and that pharmacological activation of RARγ blocked heterotopic ossification (HO), pathology in which endochondral bone forms in soft tissues. Thus, we reasoned that pharmacological inhibition of RARγ should enhance endochondral ossification, leading to a potential therapeutic strategy for bone deficiencies. We created surgical bone defects in wild type and RARγ-null mice and monitored bone healing. Fibrous, cartilaginous, and osseous tissues formed in both groups by day 7, but more cartilaginous tissue formed in mutants within and around the defects compared to controls. Next, we implanted a mixture of Matrigel and rhBMP2 subdermally to induce ectopic endochondral ossification. Administration of RARγ antagonists significantly stimulated ectopic bone formation in wild type but not in RARγ-null mice. The antagonist-induced increases in bone formation were preceded by increases in cartilage formation and were accompanied by higher levels of phosphorylated Smad1/5/8 (pSmad1/5/8) compared to vehicle-treated control. Higher pSmad1/5/8 levels were also observed in cartilaginous tissues forming in healing bone defects in RARγ-null mice, and increases in pSmad1/5/8 levels and Id1-luc activity were observed in RARγ antagonist-treated chondrogenic cells in culture. Our data show that genetic or pharmacological interference with RARγ stimulates endochondral bone formation and does so at least in part by stimulating canonical BMP signaling. This pharmacologic strategy could represent a new tool to enhance endochondral bone formation in the setting of various orthopedic surgical interventions and other skeletal deficiencies.

Original languageEnglish
JournalJournal of Orthopaedic Research
DOIs
Publication statusAccepted/In press - 2016

Fingerprint

Retinoic Acid Receptors
Osteogenesis
Pharmacology
Bone and Bones
Heterotopic Ossification
Chondrogenesis
Cartilage
Orthopedics
Cell Culture Techniques
Pathology

Keywords

  • BMP
  • Bone defect
  • Cartilage
  • Endochondral bone formation
  • RARγ

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

Cite this

Genetic and pharmacological inhibition of retinoic acid receptor γ function promotes endochondral bone formation. / Uchibe, Kenta; Son, Jiyeon; Larmour, Colleen; Pacifici, Maurizio; Enomoto-Iwamoto, Motomi; Iwamoto, Masahiro.

In: Journal of Orthopaedic Research, 2016.

Research output: Contribution to journalArticle

Uchibe, Kenta ; Son, Jiyeon ; Larmour, Colleen ; Pacifici, Maurizio ; Enomoto-Iwamoto, Motomi ; Iwamoto, Masahiro. / Genetic and pharmacological inhibition of retinoic acid receptor γ function promotes endochondral bone formation. In: Journal of Orthopaedic Research. 2016.
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