The role of protease-activated receptor-1 in bone healing.
Protease-activated receptor (PAR)-1, a G-protein-coupled receptor activated by thrombin, mediates thrombin-induced proliferation of osteoblasts. The current study was undertaken to define the role of PAR-1 in bone repair. Holes were drilled transversely through the diaphysis of both tibiae of PAR-1-null and wild-type mice. Three days later, fewer cells had invaded the drill site from adjacent bone marrow in PAR-1-null mice than in wild-type mice, and a lower percentage of cells were labeled with [(3)H]thymidine in PAR-1-null drill sites. More osteoclasts were also observed in the drill site of PAR-1-null mice than in wild-type mice 7 days after drilling. New mineralized bone area was less in the drill site and on the adjacent periosteal surface in PAR-1-null mice than in wild-type mice at day 9. From day 14, no obvious differences could be seen between PAR-1-null and wild-type tibiae. In vitro thrombin caused a dose-dependent increase in proliferation of bone marrow stromal cells isolated from wild-type mice but not PAR-1-null mice. Thrombin stimulated survival of bone marrow stromal cells from both wild-type and PAR-1-null mice, but it did not affect bone marrow stromal cell migration in either wild-type or PAR-1-null cells. The results indicate that PAR-1 plays an early role in bone repair.
Song
Shu Jun
SJ
School of Veterinary Science, University of Melbourne, Parkville, Victoria 3010, Australia.
Pagel
Charles N
CN
Campbell
Therese M
TM
Pike
Robert N
RN
Mackie
Eleanor J
EJ
D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology; D001861:Bone Regeneration; D001842:Bone and Bones / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D017931:DNA Primers / Q000737:chemistry; D005838:Genotype; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors
D017931:DNA Primers; D044463:Receptor, PAR-1; D012313:RNA; D011516:Prothrombin; D013917:Thrombin
Bone. 2001 Apr;28(4):423-9
11336924
Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1257-61
7679495
Thromb Haemost. 1995 Nov;74(5):1340-7
8607120
Blood. 1993 Mar 1;81(5):1205-13
8443381
J Orthop Res. 1993 Mar;11(2):305-12
8483044
Eur J Cell Biol. 1993 Jun;61(1):126-30
8223697
J Biol Chem. 1994 Nov 4;269(44):27372-7
7525555
Trends Pharmacol Sci. 2000 Mar;21(3):103-8
10689364
J Bone Miner Res. 2000 May;15(5):851-62
10804014
Biochemistry (Mosc). 2001 Jan;66(1):8-18
11240387
Cell Signal. 1994 Sep;6(7):743-50
7888301
Am J Physiol. 1995 May;268(5 Pt 1):C1195-201
7762612
Exp Cell Res. 1995 Aug;219(2):650-6
7641816
J Exp Med. 1996 Mar 1;183(3):821-7
8642286
Nature. 1996 Jun 6;381(6582):516-9
8632823
Blood. 1996 Nov 1;88(9):3432-45
8896408
Biochem Pharmacol. 1997 Feb 21;53(4):487-91
9105399
Brain Res Dev Brain Res. 1997 Apr 18;99(2):148-54
9125468
J Surg Res. 1997 Mar;68(2):139-44
9184672
J Biol Chem. 1998 May 8;273(19):11923-9
9565620
J Bone Miner Res. 1998 May;13(5):818-27
9610746
Nature. 1998 Aug 13;394(6694):690-4
9716134
J Biol Chem. 1999 Apr 2;274(14):9169-74
10092588
J Bone Miner Res. 1999 Aug;14(8):1320-9
10457264
Bone. 2001 Aug;29(2):134-40
11502474
Science. 2001 Aug 31;293(5535):1666-70
11533492
J Craniofac Surg. 2001 Sep;12(5):444-50
11572249
Methods. 2001 Dec;25(4):402-8
11846609
J Bone Miner Res. 2002 May;17(5):791-9
12009009
IUBMB Life. 2002 Jun;53(6):277-81
12625364
Calcif Tissue Int. 2003 Jul;73(1):49-55
14506954
Bone. 2003 Oct;33(4):733-43
14555279
Int J Biochem Cell Biol. 2005 Jan;37(1):206-13
15381162
Biosci Rep. 1983 Mar;3(3):255-61
6860783
Prostaglandins. 1986 Apr;31(4):601-8
3726153
Biochemistry. 1986 Aug 12;25(16):4622-8
3768302
Ciba Found Symp. 1988;136:42-60
3068016
Exp Hematol. 1990 May;18(4):341-7
2323369
Cell. 1991 Mar 22;64(6):1057-68
1672265
J Clin Invest. 1992 May;89(5):1469-77
1373740
Lab Anim Sci. 1992 Aug;42(4):369-74
1434497
J Clin Invest. 1993 Jan;91(1):94-8
8380817
J Cell Sci. 1995 Sep;108 ( Pt 9):3059-66
8537445