Mast cells and hypoxia drive tissue metaplasia and heterotopic ossification in idiopathic arthrofibrosis after total knee arthroplasty.
BACKGROUND
Idiopathic arthrofibrosis occurs in 3-4% of patients who undergo total knee arthroplasty (TKA). However, little is known about the cellular or molecular changes involved in the onset or progression of this condition. To classify the histomorphologic changes and evaluate potential contributing factors, periarticular tissues from the knees of patients with arthrofibrosis were analyzed for fibroblast and mast cell proliferation, heterotopic ossification, cellular apoptosis, hypoxia and oxidative stress.


RESULTS
The arthrofibrotic tissue was composed of dense fibroblastic regions, with limited vascularity along the outer edges. Within the fibrotic regions, elevated numbers of chymase/fibroblast growth factor (FGF)-expressing mast cells were observed. In addition, this region contained fibrocartilage and associated heterotopic ossification, which quantitatively correlated with decreased range of motion (stiffness). Fibrotic, fibrocartilage and ossified regions contained few terminal dUTP nick end labeling (TUNEL)-positive or apoptotic cells, despite positive immunostaining for lactate dehydrogenase (LDH)5, a marker of hypoxia, and nitrotyrosine, a marker for protein nitrosylation. LDH5 and nitrotyrosine were found in the same tissue areas, indicating that hypoxic areas within the tissue were associated with increased production of reactive oxygen and nitrogen species.


CONCLUSIONS
Taken together, we suggest that hypoxia-associated oxidative stress initiates mast cell proliferation and FGF secretion, spurring fibroblast proliferation and tissue fibrosis. Fibroblasts within this hypoxic environment undergo metaplastic transformation to fibrocartilage, followed by heterotopic ossification, resulting in increased joint stiffness. Thus, hypoxia and associated oxidative stress are potential therapeutic targets for fibrosis and metaplastic progression of idiopathic arthrofibrosis after TKA.
Freeman
Theresa A
TA
School of Biomedical Engineering and College of Drexel Medicine, Drexel University, 3120 Market Street, 323 Bossone, Philadelphia, PA 19104, USA. mjs348@drexel.edu.
Parvizi
Javad
J
Dela Valle
Craig J
CJ
Steinbeck
Marla J
MJ
J Arthroplasty. 1995 Aug;10(4):413-9
8522997
Ann Biomed Eng. 2004 Jan;32(1):50-6
14964721
Connect Tissue Res. 2001;42(1):59-69
11696989
Arthroscopy. 1997 Apr;13(2):166-71
9127073
Connect Tissue Res. 1982;9(4):263-9
6215210
Clin Orthop Relat Res. 1996 Oct;(331):216-20
8895641
J Cell Sci. 2003 May 1;116(Pt 9):1819-26
12665562
Birth Defects Res C Embryo Today. 2005 Dec;75(4):330-9
16425255
Exp Cell Res. 2001 Aug 15;268(2):189-200
11478845
Eur J Radiol. 2006 Jan;57(1):32-6
16182502
Best Pract Res Clin Rheumatol. 2006 Oct;20(5):969-81
16980218
J Exp Med. 2005 Sep 19;202(6):739-50
16157686
Curr Opin Rheumatol. 2008 Sep;20(5):565-72
18698179
Hum Pathol. 2001 Aug;32(8):842-8
11521229
Arthritis Rheum. 2007 Dec;56(12):4203-15
18050252
Curr Rheumatol Rep. 2006 Apr;8(2):145-50
16569374
Connect Tissue Res. 1982;9(3):173-9
6213370
Clin Orthop Relat Res. 1996 Oct;(331):87-92
8895623
J Appl Physiol (1985). 2003 Jan;94(1):325-34
12391033
Biochem Soc Trans. 2007 Aug;35(Pt 4):647-51
17635112
Clin Orthop Relat Res. 2002 Nov;(404):208-13
12439262
Clin Exp Metastasis. 2005;22(1):25-30
16132575
Lab Invest. 2007 Sep;87(9):858-70
17607298
Arthritis Rheum. 2001 Nov;44(11):2653-64
11710721
Arch Biochem Biophys. 1997 Jun 15;342(2):203-11
9186480
Clin Orthop Relat Res. 2000 Nov;(380):177-83
11064989
Oncol Rep. 2006 Jul;16(1):103-7
16786130
J Arthroplasty. 1990;5 Suppl:S73-7
2243220
Fibrogenesis Tissue Repair. 2009 Nov 13;2(1):5
19912645
J Bone Joint Surg Am. 2004 Jul;86(7):1479-84
15252096
J Appl Physiol (1985). 2005 Feb;98(2):715-21
15649883
J Arthroplasty. 1996 Apr;11(3):293-7
8713909
Ann N Y Acad Sci. 2006 Apr;1068:66-73
16831906
Br J Pharmacol. 2005 Jun;145(4):424-31
15806109
Arthritis Rheum. 2004 Jan;50(1):10-23
14730595
J Clin Invest. 2007 Mar;117(3):524-9
17332879
Neurourol Urodyn. 2004;23(4):374-82
15227657
J Arthroplasty. 1996 Feb;11(2):223-4
8648323
Am J Pathol. 2005 Feb;166(2):367-75
15681821
J Arthroplasty. 2004 Jun;19(4):447-52
15188102
Ann Rheum Dis. 1997 Jul;56(7):426-31
9486005
Arch Biochem Biophys. 1993 Nov 15;307(1):153-64
7694546
J Bone Joint Surg Am. 2006 Dec;88 Suppl 4:175-81
17142446
Int J Biochem Cell Biol. 2003 Dec;35(12):1601-7
12962699
Perit Dial Int. 2007 Jun;27 Suppl 2:S104-9
17556287