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.

Immunoadsorption and subsequent IgG substitution improves cardiovascular function in DCM.

This study reports that recombinant adenovirus-mediated human bone morphogenetic protein-2 gene transfer can induce mesenchymal progenitor cell differentiation and bone formation. The recombinant adenovirus with the human bone morphogenetic protein-2 gene was constructed, and mature human bone morphogenetic protein-2 expression mediated by adenovirus gene transfer was detected by specific antibody. Under adenovirus-mediated bone morphogenetic-protein gene transfer, mesenchymal progenitor cell line C3H/10T 1/2 showed cell proliferation dependent on adenovirus bone morphogenetic-protein dose. The C3H/10T 1/2 cells transduced by adenovirus bone morphogenetic protein also exhibited differentiation to osteoblast phenotype, which indicates alkaline phosphatase activity. Injection of the C3H/10T 1/2 cells into the thigh muscles of nude mice led to ossicle development detectable on radiographs. Histological analysis indicated that the new ossicles that developed in the thigh muscles of the mice had different osseous components including bone trabeculae, bone marrow, and chondrified tissue. The results of this study demonstrate the potential for gene therapy by adenovirus-mediated bone morphogenetic-protein gene transfer.

IA and subsequent IgG substitution mitigate myocardial inflammation in DCM.