Journal
CELLS
Volume 8, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/cells8060624
Keywords
osteoclast; bone resorption; hypoxia; adenosine A(2B) receptor; ATP; hypoxia-inducible factor (HIF); glycolysis; adenosine
Categories
Funding
- Arthritis Research UK [MP/19200]
- Oxford National Institute of Health Research (NIHR) Musculoskeletal Biomedical Research Unit (BRU)
Ask authors/readers for more resources
Osteoclast-mediated bone destruction is amplified in the hypoxic synovial microenvironment of rheumatoid arthritis (RA). This increased bone resorption is driven by the hypoxia-inducible transcription factor HIF. We identified hypoxic induction of the HIF-regulated adenosine A(2B) receptor in primary human osteoclasts (mRNA, 3.8-fold increase, p < 0.01) and sought to identify the role(s) of purinergic signaling via this receptor in the bone resorption process. Primary human osteoclasts were differentiated from CD14+ monocytes and exposed to hypoxia (2% O-2) and A(2B) receptor inhibitors (MRS1754, PSB603). The hypoxic increase in bone resorption was prevented by the inhibition of the A(2B) receptor, at least partly by the attenuation of glycolytic and mitochondrial metabolism via inhibition of HIF. A(2B) receptor inhibition also reduced osteoclastogenesis in hypoxia by inhibiting early cell fusion (day 3-4, p < 0.05). The A(2B) receptor is only functional in hypoxic or inflammatory environments when the extracellular concentrations of adenosine (1.6-fold increase, p < 0.05) are sufficient to activate the receptor. Inhibition of the A(2B) receptor under normoxic conditions therefore did not affect any parameter tested. Reciprocal positive regulation of HIF and the A(2B) receptor in a hypoxic microenvironment thus enhances glycolytic and mitochondrial metabolism in osteoclasts to drive increased bone resorption. A(2B) receptor inhibition could potentially prevent the pathological osteolysis associated with hypoxic diseases such as rheumatoid arthritis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available