Osteopontin deficiency impairs wear debris–induced osteolysis via regulation of cytokine secretion from murine macrophages

Abstract

Objective. To investigate the molecular mechanisms underlying particle-induced osteolysis, we focused on osteopontin (OPN), a cytokine and cellattachment protein that is associated with macrophage chemoattractant and osteoclast activation.Methods. We compared OPN protein levels in human periprosthetic osteolysis tissues with those in osteoarthritis (OA) synovial tissues. To investigate the functions of OPN during particle-induced osteolysis in vivo, titanium particles were implanted onto the calvaria of OPN-deficient mice and their wild-type (WT) littermates. Mice were killed on day 10 and evaluated immunohistologically. The effects of OPN deficiency on the secretion of inflammatory cytokines were examined using cultured bone marrow-derived macrophages (BMMs). BMMs from OPN-deficient and WT mice were cultured with titanium particles for 12 hours, and the concentrations of inflammatory cytokines in the conditioned media were measured by enzyme-linked immunosorbent assay.Results. Expression of OPN protein was enhanced in human periprosthetic osteolysis tissues as compared with OA synovial tissues. In the particle-induced model of osteolysis of the calvaria, bone resorption was significantly suppressed by OPN deficiency via inhibition of osteoclastogenesis, whereas an inflammatory reaction was observed regardless of the genotype. Results of immunostaining indicated that OPN protein was highly expressed in the membrane and bone surface at the area of bone resorption in WT mice. When BMMs were exposed to titanium particles, the concentration of proinflammatory cytokines, such as tumor necrosis factor ␣, interleukin-1␣ (IL-1␣), IL-1␤, and IL-6, as well as chemotactic factors, such as monocyte chemoattractant protein 1 and macrophage inflammatory protein 1␣, in the conditioned medium were significantly reduced by OPN deficiency. Whereas phagocytic activity of BMMs was not attenuated by OPN deficiency, phagocytosis-mediated NF-B activation was impaired in OPN-deficient BMMs. These data indicated that OPN was implicated in the development of particleinduced osteolysis via the orchestration of pro-/ antiinflammatory cytokines secreted from macrophages.Conclusion. OPN plays critical roles in wear debris-induced osteolysis, suggesting that OPN is a candidate therapeutic target for periprosthetic osteolysis.

Adenosine A 2A Receptor Activation Prevents Wear Particle–Induced Osteolysis

“…Changes in these proteins, induced by wear particles, have been described recently in the periprosthetic tissue of patients with aseptically loosened prostheses (36). Osteopontin has also been shown to be required for the progression of titanium particle–induced osteolysis in murine calvaria (37). Moreover, osteopontin may regulate TNFα secretion in the murine calvaria model of wear particle-induced bone resorption (37).…”

Cellular and Molecular Pathways Leading to External Root Resorption

“…Pretreatment with osteopontin or dentin sialoprotein has been reported to induce an increase in IL-1 (Yao et al 2008). Recent reports highlighted the fact that osteopontin is involved in osteoclast development and osteolysis, orchestrating the secretion of pro-or antiinflammatory cytokines from macrophages, as occurred with IL-1β in vivo and in vitro (Shimizu et al 2010). In humans, mechanical stress, such as orthodontic force, was shown to induce osteopontin expression by the PDL cells mediated by the Rho kinase pathway (Wongkhantee et al 2008).…”

Matricellular Proteins in the Trabecular Meshwork: Review and Update

“…229 These putative functions are more or less confirmed by phenotypic traits found in osteopontin-deficient mice, including reduced bone resorption, increased dystrophic calcification, altered sympathetic control of bone mass, impaired periprosthetic osteolysis, abnormal matrix reorganization following tissue injury, and reduced T-cell-mediated immunity. [230][231][232][233][234][235] Within the eye, osteopontin is involved in corneal and choroidal wound healing, lens epithelial injury, autoimmune uveitis, and proliferative diabetic retinopathy. [236][237][238][239][240][241][242] Using cDNA microarrays, TM cells have been shown to express osteopontin.…”