COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing.
Although a critical role of COX-2 in bone repair has been established, the mechanism involved remains unclear. During early inflammatory phase of bone healing, COX-2 is produced by the surrounding inflammatory cells as well as bone/cartilage progenitors. Based on the temporal and spatial expression of COX-2 during the early phase of fracture healing, we hypothesize that COX-2 from both sources is critical for progenitor cell activation, proliferation and differentiation. To directly test this we utilized a murine femoral grafting model, in which live segmental grafts from the same strains were transplanted and donor versus host cell involvement in healing was assessed. Specifically, fresh femur cortical bone grafts of 4 mm in length from COX-2(-/-) (KO) mice were transplanted into wild type (WT) mice with the same sized segmental defect in femurs. Similarly, grafts from WT were transplanted into the defects in KO mice. As controls, transplantations between wild types, and transplantations between KO were also performed. Histologic analyses showed that WT-to-WT transplantation resulted in normal endochondral bone healing as evidenced by markedly induction of neovascularization and periosteal bone formation on donor graft. In contrast, transplantation of KO graft into KO host led to 96% reduction of bone formation and near elimination of donor cell-initiated periosteal bone formation. Similarly, transplantation of WT graft into a KO host resulted in 87% reduction of bone formation (n=8, p>0.05), indicating that KO host impaired WT donor progenitor cell expansion and differentiation. When a KO graft was transplanted into WT host, KO donor periosteal cell-initiated endochondral bone formation was restored. Histomorphometric analyses demonstrated 10-fold increase in bone formation and 3-fold increase in cartilage formation compared to KO-to-KO transplantation (n=8, p<0.05), suggesting that COX-2 deficient donor cells were capable to differentiate and form bone when placed in a WT host. Taken together, our data strongly suggest that COX-2 is critical for initiation of periosteal cortical bone healing. The early induction of COX-2 constitutes a crucial host-healing environment for activation and differentiation of donor periosteal progenitors. Elimination of COX-2 at the early stage of healing could lead to detrimental effects on periosteal progenitor cell-initiated cortical bone repair.
Xie
Chao
C
Center for Musculoskeletal Research, University of Rochester Medical Center, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Ming
Xue
X
Wang
Qun
Q
Schwarz
Edward M
EM
Guldberg
Robert E
RE
O'Keefe
Regis J
RJ
Zhang
Xinping
X
D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000166:cytology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D017931:DNA Primers; D017102:Fracture Healing; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*; D014057:Tomography, X-Ray Computed
D017931:DNA Primers; D051546:Cyclooxygenase 2
Orthopedics. 2000 Jul;23(7 Suppl):S765-8
10914696
Curr Opin Investig Drugs. 2005 May;6(5):461-6
15912958
J Bone Miner Res. 2009 Feb;24(2):251-64
18847332
J Bone Miner Res. 2002 Jun;17(6):963-76
12054171
Nat Med. 1999 Jun;5(6):698-701
10371510
Annu Rev Biochem. 2000;69:145-82
10966456
Biochim Biophys Acta. 1996 Jan 5;1299(1):125-40
8555245
Am J Physiol Heart Circ Physiol. 2004 Jul;287(1):H302-10
15016633
J Cell Physiol. 2008 Feb;214(2):405-12
17657727
Nat Med. 2005 Mar;11(3):291-7
15711561
Bone. 2004 Nov;35(5):1003-12
15542024
Biochem Pharmacol. 1999 Oct 15;58(8):1237-46
10487525
Prostaglandins Leukot Essent Fatty Acids. 2005 Feb;72(2):89-93
15626591
J Bone Miner Res. 2007 Feb;22(2):286-97
17087627
J Orthop Res. 2002 Jan;20(1):159-62
11853083
Nature. 1995 Nov 23;378(6555):406-9
7477380
Am J Pathol. 2004 Nov;165(5):1663-76
15509536
Clin Orthop Relat Res. 1989 Nov;(248):283-93
2680202
Clin Orthop Relat Res. 2001 Oct;(391 Suppl):S190-207
11603704
Gastroenterology. 1997 Feb;112(2):387-97
9024292
J Bone Miner Res. 1999 Nov;14(11):1805-15
10571679
J Biol Chem. 1982 Jul 25;257(14):8098-105
6177695
J Bone Miner Res. 2005 Dec;20(12):2124-37
16294266
Clin Orthop Relat Res. 1989 Nov;(248):294-309
2680203
J Bone Miner Res. 2001 Apr;16(4):660-70
11315993
Cell. 1995 Nov 3;83(3):473-82
8521477
J Orthop Trauma. 1995;9(5):392-400
8537842
J Bone Joint Surg Br. 2000 Jul;82(5):655-8
10963160
Gastroenterology. 2005 May;128(5):1445-61
15887126
J Orthop Res. 2004 Nov;22(6):1254-60
15475206
Clin Orthop Relat Res. 1989 Apr;(241):265-77
2647335
J Cell Biochem. 2003 Apr 1;88(5):873-84
12616527
J Orthop Res. 2001 Jan;19(1):78-84
11332624
J Bone Joint Surg Am. 2007 Mar;89(3):500-11
17332098
J Bone Miner Res. 2003 Jun;18(6):949-54
12817746
J Orthop Res. 2003 Jul;21(4):670-5
12798067
Biochem Pharmacol. 1999 Sep 15;58(6):983-90
10509750
Ann N Y Acad Sci. 2006 Apr;1068:532-42
16831949
J Clin Invest. 2002 Jun;109(11):1405-15
12045254