The endocannabinoid system and retinoic acid signaling combine to influence bone growth

Daniel Fraher; Robert J Mann; Matthew J Dubuisson; Megan K Ellis; Tingsheng Yu; Ken Walder; Alister C Ward; Christoph Winkler; Yann Gibert

doi:10.1016/j.mce.2021.111267

The endocannabinoid system and retinoic acid signaling combine to influence bone growth

Mol Cell Endocrinol. 2021 Jun 1:529:111267. doi: 10.1016/j.mce.2021.111267. Epub 2021 Apr 9.

Authors

Daniel Fraher¹, Robert J Mann¹, Matthew J Dubuisson², Megan K Ellis¹, Tingsheng Yu³, Ken Walder¹, Alister C Ward¹, Christoph Winkler³, Yann Gibert⁴

Affiliations

¹ Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, Deakin University School of Medicine, Geelong, VIC, 3216, Australia.
² University of Mississippi Medical Center, Dept of Cell and Molecular Biology, 2500 North State Street, Jackson, MS, 39216, USA.
³ Department of Biological Sciences and Centre for Bioimaging Sciences, National University of Singapore, Singapore.
⁴ Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, Deakin University School of Medicine, Geelong, VIC, 3216, Australia; University of Mississippi Medical Center, Dept of Cell and Molecular Biology, 2500 North State Street, Jackson, MS, 39216, USA. Electronic address: [email protected].

Abstract

Osteoporosis is an increasing burden on public health as the world-wide population ages and effective therapeutics are severely needed. Two pathways with high potential for osteoporosis treatment are the retinoic acid (RA) and endocannabinoid system (ECS) signaling pathways. We sought to elucidate the roles that these pathways play in bone development and maturation. Here, we use chemical treatments to modulate the RA and ECS pathways at distinct early, intermediate, and late times bone development in zebrafish. We further assessed osteoclast activity later in zebrafish and medaka. Finally, by combining sub-optimal doses of AR and ECS modulators, we show that enhancing RA signaling or reducing the ECS promote bone formation and decrease osteoclast abundance and activity. These data demonstrate that RA signaling and the ECS can be combined as sub-optimal doses to influence bone growth and may be key targets for potential therapeutics.

Keywords: Endocannabinoid; Medaka; Osteoblast; Osteoclast; Retinoic acid; Zebrafish.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Development / drug effects
Bone Development / genetics
Embryo, Nonmammalian
Endocannabinoids / metabolism*
Gene Expression Regulation, Developmental
Oryzias / genetics*
Oryzias / growth & development
Oryzias / metabolism
Osteoclasts / cytology
Osteoclasts / drug effects
Osteoclasts / metabolism
Osteogenesis / drug effects
Osteogenesis / genetics
Osteonectin / genetics
Osteonectin / metabolism
Rimonabant / pharmacology
Signal Transduction / genetics*
Sp7 Transcription Factor / genetics
Sp7 Transcription Factor / metabolism
Transcription Factors / genetics*
Transcription Factors / metabolism
Tretinoin / metabolism*
Tretinoin / pharmacology
Zebrafish / genetics*
Zebrafish / growth & development
Zebrafish / metabolism
Zebrafish Proteins / genetics*
Zebrafish Proteins / metabolism

Substances

Endocannabinoids
Osteonectin
Runx2a protein, zebrafish
Runx2b protein, zebrafish
Sp7 Transcription Factor
Transcription Factors
Zebrafish Proteins
sp7 protein, zebrafish
Tretinoin
Rimonabant

Grants and funding

P20 GM104357/GM/NIGMS NIH HHS/United States