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Activation of protease-activated receptor-2 leads to inhibition of osteoclast differentiation.
- Source :
-
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2004 Mar; Vol. 19 (3), pp. 507-16. Date of Electronic Publication: 2003 Dec 22. - Publication Year :
- 2004
-
Abstract
- Unlabelled: 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.<br />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.<br />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.<br />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.<br />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.
- Subjects :
- Animals
Bone Marrow Cells cytology
Carrier Proteins metabolism
Cell Differentiation drug effects
Cell Line
Cells, Cultured
Cyclooxygenase 1
Cyclooxygenase 2
Interleukin-6 metabolism
Isoenzymes metabolism
Macrophages cytology
Macrophages metabolism
Membrane Glycoproteins metabolism
Membrane Proteins
Mice
Osteoblasts cytology
Osteoclasts cytology
Prostaglandin-Endoperoxide Synthases metabolism
RANK Ligand
Receptor Activator of Nuclear Factor-kappa B
Osteoclasts metabolism
Receptor, PAR-2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0884-0431
- Volume :
- 19
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
- Publication Type :
- Academic Journal
- Accession number :
- 15040840
- Full Text :
- https://doi.org/10.1359/JBMR.0301248