The role of osteoclast differentiation in aseptic loosening

Abstract

The major cause of orthopaedic implant loosening is thought to be accelerated osteoclastic bone resorption due to the action of cytokines produced in response to phagocytosis of implant-derived wear particles. This accelerated osteoclastic bone resorption could be due to increases in any of the following processes: recruitment of osteoclast precursors to the local microeiivironment, differentiation of precursors into mature multinucleated osteoclasts, activation of mature osteoclasts, and/or survival of osteoclasts. Our studies have focused on differentiation and survival to complement work by others who have focused on recruitment of precursors and activation. Taken together, our studies and those of other investigators provide strong evidence that increased recruitment of osteoclast precursors and their subsequent differentiation play major roles in wear particle-induced osteolysis. In contrast, increased osteoclast activation and survival appear to play minor roles. These studies suggest that development of therapeutic interventions that reduce either recruitment or differentiation of osteoclast precursors would improve the performance of orthopaedic implants.

Do Genetic Susceptibility, Toll-like Receptors, and Pathogen-associated Molecular Patterns Modulate the Effects of Wear?

“…Those associations with aseptic loosening, in combination with those in genes that encode for proinflammatory cytokines, confirm the well-accepted concept [35,38,75,108] that aseptic loosening is primarily driven by the following stepwise process: (1) wear particles induce production of proinflammatory cytokines; (2) the proinflammatory cytokines stimulate production of RANKL; (3) RANKL increases osteoclast differentiation; and (4) the increased number of osteoclasts causes local osteolysis.…”

Erythromycin inhibits wear debris‐induced inflammatory osteolysis in a murine model

“…There is accumulating evidence to indicate that enhanced osteoclastogenesis is a hallmark of AL. 5,12,29 The expression of mRNA encoding RANKL and RANK in periprosthetic tissues is usually associated with focal bone loss near the loose prosthesis. 11 Abnormally higher levels of RANKL (mRNA and protein) were predominantly associated with cells containing wear particles, and may significantly contribute to the development of AL.…”

Protective effects of IL-1Ra or vIL-10 gene transfer on a murine model of wear debris-induced osteolysis

“…36 Several studies have indicated that osteoclasts are the main cells in bone resorption of aseptic loosening. 2,[37][38][39] Recently, two essential regulators have been identified in osteoclastogenesis: M-CSF and RANKL. 40,41 In vitro studies have shown that in the presence of M-CSF, exogenous RANK ligand effectively induced osteoclast differentiation of progenitors derived from mouse bone marrow cells, spleen cells, or human peripheral blood mononuclear cells in the absence of stromal cells/osteoblastic cells.…”