Adenosine stimulates IL-6 but inhibits osteoprotegerin secretion by osteoprogenitor cells
BAJ Evans1, C Elford1 & J Ham2
Nucleotide receptors can be classified into two groups: P1 receptors where adenosine is the primary ligand, and P2 receptors where the main ligands are ATP, ADP, UTP and UDP. The presence of the P2 family members in osteoblasts and osteoclasts has been known for some time, but there have been no published studies on the role of adenosine in bone physiology.
We have demonstrated the presence of the four P1 adenosine receptor subtypes (A1, A2A, A2B and A3) in a human osteoprogenitor cell line (HCC1). We have also investigated the effect of selective adenosine agonists (0 - 10 microM) for each receptor subtype on IL-6 secretion. NECA (1 microM), a non-specific adenosine receptor agonist stimulated a 10-fold increase in IL-6 secretion with an EC50 of 100 nM. A 10-fold higher concentration of adenosine, CCPA (A1 agonist) and IB-MECA (A3 agonist) stimulated 1L-6 secretion by 2.5-, 2-, and 3.5-fold respectively. CGS21860 (A2A agonist) had no effect, whilst forskolin also stimulated IL-6 secretion. The effects of 100 microM NECA, adenosine and CGS21860 (13-, 5-, and 2-fold increase respectively) on cAMP stimulation paralleled that for IL-6 secretion and suggest that the functionally dominant receptor is the A2B subtype. Furthermore, adenosine, NECA, CGS21860 and CCPA, but not IB-MECA inhibited the production of osteoprotegerin. Other work (RT-PCR and immunocytochemistry) demonstrated that HCC1, primary bone marrow and MG63 cells express ecto 5'-nucleotides, and that primary bone marrow and MG63, but not HCC1 cells, express adenosine deaminase
Our data supports a role for adenosine and the P1 receptors in the function of osteoprogenitor cells and osteoblasts. This might be especially important in conditions such as rheumatoid arthritis, where high level of adenosine may play a role in the cross talk between osteoblasts and osteoclasts, as well as have direct effects on osteoblast and osteoclast differentiation and activity.