Review Question - QID 212908

In macrophage-activated osteoclastogenesis and osteolysis, TNF-alpha is released by macrophages, leading to the activation of osteoclasts and eventual bone resorption.

Aseptic loosening after THA is the most common cause of late failure and typically is the result of osteolysis. This process begins with the generation of polyethylene wear particles, which then activates macrophages. Particles smaller than 1 micron, or submicron, are most reactive to macrophage-induced osteolysis. Once activated, macrophages produce TNF-alpha and IL-1, among other cytokines, which in turn promotes RANK-RANKL pathway signaling. RANK, receptor activator of nuclear factor kappa-beta, activation leads to transcription factors that induce gene expression for osteoclastogenesis and osteoclast activation.

Holt et al. reviewed the literature regarding cell signaling molecules involved in osteolysis. The most important mediators reported were TNF-alpha and IL-1, which many studies documented the potentiation of each other during the process. Several studies reported these molecules to be present in high concentrations in the surrounding pseudomembranes in revision arthroplasty.

Azuma et al. performed a study that involved bone marrow macrophage cells cultured with mouse tibia and femur in the presence of several inflammatory cytokines. Bone resorption assay indicated that the presence of TNF-alpha and M-CSF were crucial to the differentiation of osteoclasts and play an important role in osteolysis.

Figure A demonstrates a frog-leg lateral of the right hip demonstrating extensive periacetabular osteolysis along with the eccentric position of the femoral head within the acetabulum. Illustration A depicts a diagram of TNF-alpha and IL-1 activation of the RANK-RANKL pathway that leads to osteoclastogenesis and bone resorption.

Incorrect Answers:
Answer 2: RANKL is produced by osteoblasts, not osteoclasts.
Answer 3: Osteoprotegerin binds to RANKL, not RANK. It is a soluble inhibitor molecule that acts as a competitive inhibitor to binding with RANK.
Answer 4: The upregulation of the NF-kappa transcription factor is the direct result of RANK-RANKL signaling and leads to gene expression that promotes osteoclastogenesis and bone resorption.
Answer 5: Interleukins that signal osteolysis are not released by osteoclasts, but rather macrophages.