Parts of this work were presented at the Annual Scientific Meeting of the Australian and New Zealand Bone and Mineral Society, Coolum, Australia, June 10–13, 2003, and the 30th European Symposium on Calcified Tissues, Rome, Italy, May 8-12, 2003.
Activation of Protease-Activated Receptor-2 Leads to Inhibition of Osteoclast Differentiation†
Article first published online: 22 DEC 2003
Copyright © 2004 ASBMR
Journal of Bone and Mineral Research
Volume 19, Issue 3, pages 507–516, March 2004
How to Cite
Smith, R., Ransjö, M., Tatarczuch, L., Song, S.-J., Pagel, C. N., Morrison, J. R., Pike, R. N. and Mackie, E. J. (2004), Activation of Protease-Activated Receptor-2 Leads to Inhibition of Osteoclast Differentiation. J Bone Miner Res, 19: 507–516. doi: 10.1359/JBMR.0301248
The authors have no conflict of interest.
- Issue published online: 2 DEC 2009
- Article first published online: 22 DEC 2003
- Manuscript Accepted: 8 OCT 2003
- Manuscript Revised: 12 SEP 2003
- Manuscript Received: 16 JUL 2003
- protease-activated receptor-2;
- osteoclast differentiation;
- prostaglandin G/H synthase;
PAR-2 is expressed by osteoblasts and activated by proteases present during inflammation. PAR-2 activation inhibited osteoclast differentiation induced by hormones and cytokines in mouse bone marrow cultures and may protect bone from uncontrolled resorption.
Introduction: Protease-activated receptor-2 (PAR-2), which is expressed by osteoblasts, is activated specifically by a small number of proteases, including mast cell tryptase and factor Xa. PAR-2 is also activated by a peptide (RAP) that corresponds to the “tethered ligand” created by cleavage of the receptor's extracellular domain. The effect of activating PAR-2 on osteoclast differentiation was investigated.
Materials and Methods: Mouse bone marrow cultures have been used to investigate the effect of PAR-2 activation on osteoclast differentiation induced by parathyroid hormone (PTH), 1,25 dihydroxyvitamin D3 [1,25(OH)2D3], and interleukin-11 (IL-11). Expression of PAR-2 by mouse bone marrow, mouse bone marrow stromal cell-enriched cultures, and the RAW264.7 osteoclastogenic cell line was demonstrated by RT-PCR.
Results: RAP was shown to inhibit osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL-11. Semiquantitative RT-PCR was used to investigate expression of mediators of osteoclast differentiation induced by PTH, 1,25(OH)2D3, or IL-11 in mouse bone marrow cultures and primary calvarial osteoblast cultures treated simultaneously with RAP. In bone marrow and osteoblast cultures treated with PTH, 1,25(OH)2D3, or IL-11, RAP inhibited expression of RANKL and significantly suppressed the ratio of RANKL:osteoprotegerin expression. Activation of PAR-2 led to reduced expression of prostaglandin G/H synthase-2 in bone marrow cultures treated with PTH, 1,25(OH)2D3, or IL-11. RAP inhibited PTH- or 1,25(OH)2D3-induced expression of IL-6 in bone marrow cultures. RAP had no effect on osteoclast differentiation in RANKL-treated RAW264.7 cells.
Conclusion: These observations indicate that PAR-2 activation inhibits osteoclast differentiation by acting on cells of the osteoblast lineage to modulate multiple mediators of the effects of PTH, 1,25(OH)2D3, and IL-11. Therefore, the role of PAR-2 in bone may be to protect it from uncontrolled resorption by limiting levels of osteoclast differentiation.