muramidase and Osteolysis

Maintenance of healthy bone requires the balanced activities of osteoclasts (OCs), which resorb bone, and osteoblasts, which build bone. Disproportionate action of OCs is responsible for the bone loss associated with postmenopausal osteoporosis and rheumatoid arthritis. NF-κB inducing kinase (NIK) controls activation of the alternative NF-κB pathway, a critical pathway for OC differentiation. Under basal conditions, TRAF3-mediated NIK degradation prevents downstream signaling, and disruption of the NIK:TRAF3 interaction stabilizes NIK leading to constitutive activation of the alternative NF-κB pathway.. Using transgenic mice with OC-lineage expression of NIK lacking its TRAF3 binding domain (NT3), we now find that alternative NF-κB activation enhances not only OC differentiation but also OC function. Activating NT3 with either lysozyme M Cre or cathepsinK Cre causes high turnover osteoporosis with increased activity of OCs and osteoblasts. In vitro, NT3-expressing precursors form OCs more quickly and at lower doses of RANKL. When cultured on bone, they exhibit larger actin rings and increased resorptive activity. OC-specific NT3 transgenic mice also have an exaggerated osteolytic response to the serum transfer model of arthritis.. Constitutive activation of NIK drives enhanced osteoclastogenesis and bone resorption, both in basal conditions and in response to inflammatory stimuli.

Topics: Animals; Arthritis; Binding Sites; Blotting, Western; Bone Density; Bone Marrow Cells; Cathepsin K; Cells, Cultured; Female; Macrophages; Male; Mice; Mice, Transgenic; Muramidase; NF-kappa B; NF-kappaB-Inducing Kinase; Osteocalcin; Osteoclasts; Osteolysis; Osteoporosis; Protein Binding; Protein Serine-Threonine Kinases; RANK Ligand; Reverse Transcriptase Polymerase Chain Reaction; TNF Receptor-Associated Factor 3

Polymethylmethacrylate (PMMA) is clinically employed in a wide range of orthopaedic procedures. The etiology of the inflammatory reaction of recipient tissues to PMMA remains unresolved. Classically, polymorphonuclear leukocytes (PMNs) release cytoplasmic lysosomal granules when exposed to a variety of proinflammatory stimuli. Such degranulation contributes, and partially defines, the local tissue reaction to this foreign material. In the present investigation, PMMA particles (50-60 nm) were mixed with human PMNs, and the amount of lactate dehydrogenase, lysozyme, and beta-glucuronidase released from the cells was quantitated. In all cases, a dose-dependent increase in degranulation followed the addition of increasing amounts of PMMA to the PMNs. In addition, the migration of PMNs was diminished in a dose-dependent manner with exposure to increasing amounts of the cement. These results suggested that PMMA stimulates the release of leukocyte lysosomal contents and alters the migration characteristics of these cells in a manner that is consistent with the local inflammatory reaction to this cement.

Topics: Biocompatible Materials; Chemotaxis, Leukocyte; Glucuronidase; Humans; In Vitro Techniques; Kinetics; L-Lactate Dehydrogenase; Lysosomes; Methylmethacrylates; Microspheres; Models, Biological; Muramidase; Neutrophils; Osteolysis; Polystyrenes; Prostheses and Implants

Topics: Arthritis; Female; Fingers; Histiocytes; Humans; Immunoenzyme Techniques; Lymphatic Diseases; Middle Aged; Muramidase; Osteolysis; Radiography; Skin; Skin Neoplasms