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Dopamine suppresses osteoclast differentiation via cAMP/PKA/CREB pathway.
- Source :
-
Cellular Signalling . Feb2021, Vol. 78, pN.PAG-N.PAG. 1p. - Publication Year :
- 2021
-
Abstract
- How the nervous system regulates bone remodeling is an exciting area of emerging research in bone biology. Accumulating evidence suggest that neurotransmitter-mediated inputs from neurons may act directly on osteoclasts. Dopamine is a neurotransmitter that can be released by hypothalamic neurons to regulate bone metabolism through the hypothalamic-pituitary-gonadal axis. Dopamine is also present in sympathetic nerves that penetrate skeletal structures throughout the body. It has been shown that dopamine suppresses osteoclast differentiation via a D2-like receptors (D2R)-dependent manner, but the intracellular secondary signaling pathway has not been elucidated. In this study, we found that cAMP-response element binding protein (CREB) activity responds to dopamine treatment during osteoclastogenesis. Considering the critical role of CREB in osteoclastogenesis, we hypothesize that CREB may be a critical target in dopamine's regulation of osteoclast differentiation. We confirmed that D2R is also present in RAW cells and activated by dopamine. Binding of dopamine to D2R inhibits the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway which ultimately decreases CREB phosphorylation during osteoclastogenesis. This was also associated with diminished expression of osteoclast markers that are downstream of CREB. Pharmacological activation of adenylate cyclase (to increase cAMP production) and PKA reverses the effect of dopamine on CREB activity and osteoclastogenesis. Therefore, we have identified D2R/cAMP/PKA/CREB as a candidate pathway that mediates dopamine's inhibition of osteoclast differentiation. These findings will contribute to our understanding of how the nervous and skeletal systems interact to regulate bone remodeling. This will enable future work toward elucidating the role of the nervous system in bone development, repair, aging, and degenerative disease. Unlabelled Image • We identified a candidate pathway (D2R/cAMP/PKA/CREB) that mediates dopamine's regulation of osteoclast differentiation. • Pharmacological activation of cAMP/PKA/CREB pathway reverses dopamine's inhibition of osteoclastogenesis. • Dopamine and CREB may be promising mediators of neuronal regulation of bone remodeling. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 08986568
- Volume :
- 78
- Database :
- Academic Search Index
- Journal :
- Cellular Signalling
- Publication Type :
- Academic Journal
- Accession number :
- 147792177
- Full Text :
- https://doi.org/10.1016/j.cellsig.2020.109847