Inhibition of leukotriene function can modulate particulate‐induced changes in bone cell differentiation and activity

Abstract

Aseptic loosening remains the major problem facing arthroplasty longevity with particulates from component materials touted as the cause of periprosthetic osteolysis. Proposed mechanisms in aseptic bone loss include: increased resorption, increased differentiation of osteoclasts (and/or macrophages locally), and decreased osteoblastic bone formation. Leukotrienes participate in osteoclastic bone resorption. We investigated inhibiting leukotrienes synthesis, using ICI 230487, to ameliorate the effects of particulates on osteoclast pit formation and also assessed the effects of alendronate, a bisphosphonate, on pit formation. Three particulates were used: ultra high molecular weight polyethylene (UHMWPE), polymethylmethacrylate (PMMA) and hydroxyapatite (HA). Osteoclast resorption was increased with UHMWPE, PMMA, and HA particles. Interventions with alendronate and ICI 230487 reduced particulate-induced osteoclast resorption. Both ICI 230487 and alendronate reduced osteoclast numbers at higher doses. To assess the effect of particulates on osteoclast and macrophage differentiation, mouse bone marrow was cultured and stained for tartrate resistant acid phosphatase colonies (TRAP+, osteoclasts) and nonspecific esterase positive colonies (NSE+, macrophage precursors). Particulates increased both TRAP+ and NSE+ colony formation. These increases were inhibited by ICI 230487. Particulates also inhibited osteoblast function assessed by the development of mineralized nodules and alkaline phosphatase positive (AP+) colony area. ICI 230487 partly protected osteoblast function from this particulate effect. Blockade of leukotriene production may prove a useful therapeutic intervention for particulate-induced aseptic loosening by inhibiting resorptive activity, reducing the pro-inflammatory cell populations induced and recruited by these particulates, as well as ameliorating the negative effects of inflammatory mediators on osteoblast function.

Runx2 promotes both osteoblastogenesis and novel osteoclastogenic signals in ST2 mesenchymal progenitor cells

“…A role for leukotrienes in bone metabolism is strongly suggested by the increased cortical bone thickness and the partial skeletal resistance to ovariectomy observed in mice deficient for 5-Lipoxygenase (5-LO), the enzyme that catalyzes the first step in leukotriene synthesis from arachidonic acid [78]. Furthermore, 5-LO inhibitors attenuate osteoclast differentiation and bone resorption in vitro [79, 80]. The product of the reaction catalyzed by 5-LO, Leukotriene A4 (LTA4), is either hydrolyzed to yield LTB4, which is involved in immune cells chemotaxis, or is conjugated with reduced glutathione to yield Leukotriene C4 (LTC4), a reaction catalyzed by LTC4 Synthase ( Ltc4s ) [81].…”

The effect of bisphosphonates and titanium particles on osteoblasts

“…Particles also inhibited the function of osteoblast as shown by a reduction in the development of mineralised nodules and in the area of ALP-positive colonies. 22 Few studies have evaluated the simultaneous effect of bisphosphonates and particles. One showed that by mixing a bisphosphonate with bone cement, it was possible to inhibit resorption caused by polymethylmethacrylate particles.…”

Effect of Alendronate on Osteoclast Differentiation and Bone Volume in Transplanted Bone

“…Furthermore, osteoclast apoptosis may occur as a result of treatment with any of the biphosphonate fam-alendronate to the bone resorption mechanisms may depend on the dose of drug and schedule of administration [1,6]. The present study suggests that the bone resorption in the early stages of bone transplantation is controlled by local action of alendronate.…”