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. 1999 Jan;154(1):203-10.
doi: 10.1016/s0002-9440(10)65266-2.

Tumor necrosis factor-alpha mediates orthopedic implant osteolysis

K D Merkel  1 , J M Erdmann, K P McHugh, Y Abu-Amer, F P Ross, S L Teitelbaum
Affiliations

Tumor necrosis factor-alpha mediates orthopedic implant osteolysis

K D Merkel et al. Am J Pathol. 1999 Jan.

Abstract

Osteolysis complicating arthroplasty reflects progressive generation of implant-derived wear particles, which prompt an inflammatory reaction attended by recruitment of osteoclasts to the prosthesis-bone interface. To identify a soluble mediator of periprosthetic osteolysis we first showed that implant particles induce c-src in murine bone marrow macrophages (BMMs), a protein specifically expressed when these cells commit to the osteoclast phenotype. The fact that tumor necrosis factor-alpha (TNF) is a potent osteoclastogenic agent while at the same time is the only soluble moiety known to be c-src inductive suggests that this cytokine may mediate implant particle-induced osteoclastogenesis. Consistent with this hypothesis, prosthesis-derived wear particles, recovered at revision arthroplasty, dose-dependently prompt TNF secretion by BMMs. Similarly, particulate polymemthylmethacrylate, the major component of orthopedic implant cement, induces BMM expression of TNF mRNA and protein in a time- and dose-dependent manner. Furthermore, failure of BMMs derived from mice deleted of both the p55 and p75 TNF receptors to express c-src in response to polymemthyl-methacrylate indicates TNF is an essential mediator of particle induction of this osteoclast specific protein. To test the hypothesis that TNF mediates implant osteolysis, we established an in vivo murine model of this condition that histologically mirrors that of man. Verifying that TNF is essential to development of particle osteolysis, mice failing to express both the p55 and p75 TNF receptors are protected from the profound bone resorption attending polymemthyl-methacrylate particle implantation on calvariae of wild-type animals. Finally, the protective effect of deletion of both TNF receptors is recapitulated in mice lacking only the p55 receptor. Thus, targeting TNF and/or its p55 receptor may arrest wear particle osteolysis.

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Figures

Figure 1.
Figure 1.
Periprosthetic wear particles induce c-src expression. BMMs, derived from endotoxin resistant C3H/HeJ mice and precultured 4 days, were maintained for 24 hrs ± particles (108/ml isolated from periprosthetic tissues obtained at revision arthroplasty). The cells were lysed and equal amounts of protein analyzed by immunoblot for c-src content.
Figure 2.
Figure 2.
Periprosthetic wear particles induce TNF expression. C3H/HeJ BMMs were precultured for 72 hours after which they were exposed to increasing numbers of retrieved wear particles. Secreted TNF was measured by ELISA 24 hours later.
Figure 3.
Figure 3.
PMMA particles induce TNF mRNA and protein in a dose-dependent manner. C3H/HeJ BMMs were precultured for 72 hours after which they were exposed to increasing amounts of PMMA particles. RNA was extracted and probed with a TNF cDNA (upper panel) 24 hours later. Secreted TNF was measured by ELISA (lower panel). The values represent the means of two assays. The negative values for control and 0.2 mg/ml PMMA reflect the sensitivity of the assay relative to the background.
Figure 4.
Figure 4.
PMMA particles induce TNF mRNA and protein in a time-dependent manner. C3H/HeJ BMMs were precultured for 72 hours and exposed to 2 mg/ml PMMA. RNA was extracted with time and probed with a TNF cDNA (upper panel). Secreted TNF was measured by ELISA (lower panel).
Figure 5.
Figure 5.
PMMA transcriptionally activates the TNF gene. J774A.1 murine macrophages were exposed overnight to 2 mg/ml PMMA. The cells were washed and transfected with TNF(−1059)CAT reporter construct containing the full length (−1059 nt.) murine TNF promoter. After 23 hours they were lysed, and the lysate assayed for CAT activity. To control for transfection efficiency, all data were normalized to pMB3–675Luc, containing the first 675 nt. of the murine B3 integrin promoter.
Figure 6.
Figure 6.
PMMA does not induce c-src in BMMs lacking TNF receptors. Wild type (p55+/+p75+/+TNFr) and TNF receptor-deleted (p55−/−p75−/−TNFr) BMMs were exposed for 24 hours to PMMA (2 mg/ml). Equal amounts of lysate protein were immunoblotted with anti-c-src monoclonal antibody.
Figure 7.
Figure 7.
Mice lacking both TNFrs are protected from implant osteolysis. Original ×40 (A) and ×160 (B) magnification of calvaria of three pairs of littermates of p55+/+p75+/+ and p55−/−p75−/−TNFr mice in which 30 mg of PMMA was placed beneath the external periosteum. One week later the animals were sacrificed and histological sections, taken 2 to 3 mm lateral to the midsagittal suture, stained for TRAP activity. An inflammatory reaction with numerous osteoclasts (red-staining cells) that resorb though the calvarium occurs only in TNFr intact animals (p55+/+p75+/+TNFr) implanted with PMMA particles. Although double TNFr deleted mice (p55−/−/p75−/−TNFr) form an inflammatory membrane in response to PMMA particles, there is no evidence of enhanced osteoclastogenesis or bone resorption.
Figure 7.
Figure 7.
Mice lacking both TNFrs are protected from implant osteolysis. Original ×40 (A) and ×160 (B) magnification of calvaria of three pairs of littermates of p55+/+p75+/+ and p55−/−p75−/−TNFr mice in which 30 mg of PMMA was placed beneath the external periosteum. One week later the animals were sacrificed and histological sections, taken 2 to 3 mm lateral to the midsagittal suture, stained for TRAP activity. An inflammatory reaction with numerous osteoclasts (red-staining cells) that resorb though the calvarium occurs only in TNFr intact animals (p55+/+p75+/+TNFr) implanted with PMMA particles. Although double TNFr deleted mice (p55−/−/p75−/−TNFr) form an inflammatory membrane in response to PMMA particles, there is no evidence of enhanced osteoclastogenesis or bone resorption.
Figure 8.
Figure 8.
Particle-induced osteolysis is mediated via the p55TNFr. PMMA (30 mg) was placed beneath the external calvarial periosteum of p55+/+/p75+/+ and p55 −/−/p75+/+ TNFr mice. One week later the animals were sacrificed and histological sections, taken 2 to 3 mm lateral to the midsagital section, stained for TRAP activity. Although pp55−/−/p75+/+ mice develop an inflammatory reaction in response to PMMA like p55−/−/p75−/− mice, there is no evidence of osteoclastogenesis or bone resorption.
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