Effects of CB2 and TRPV1 Stimulation on Osteoclast Overactivity Induced by Iron in Pediatric Inflammatory Bowel Disease

Abstract

Background The reduction of bone mineral density and osteoporosis have high impacts on the health of patients with inflammatory bowel diseases (IBD). We have previously shown that a dysregulated iron metabolism occurs in IBD and leads to a decrease in circulating iron concentration and excessive intracellular sequestration of iron. Studies suggest that iron overload significantly affects the bone, accelerating osteoclast (OC) differentiation and activation, promoting bone resorption. Moreover, we demonstrated that iron overload causes OC overactivity. The cannabinoid receptor type 2 (CB2) and the transient receptor potential vanilloid type-1 (TRPV1) are potential therapeutic targets for bone diseases. The aim of this study was to evaluate the roles of CB2 and TRPV1 receptors and of iron in the development of osteoporosis in pediatric IBD. Methods We differentiated OCs from peripheral blood mononuclear cells of patients with IBD and healthy donors and evaluated CB2 and TRPV1 receptor expression; OC activity, and iron metabolism by Western blot, TRAP assays, bone resorption assays, and iron assays. Moreover, we analyzed the effects of the pharmacological modulation of CB2 and TRPV1 receptors on OC activity and on the iron metabolism. Results We confirmed the well-known roles of CB2 and TRPV1 receptors in bone metabolism and suggested that their stimulation can reduce the OC overactivity induced by iron, providing new insights into the pathogenesis of pediatric IBD-related bone resorption. Conclusions Stimulation of CB2 and TRPV1 could reduce IBD-related osteoporosis due to their direct effects on OC activity and to modulating the iron metabolism.

CB2 Receptor as Emerging Anti-Inflammatory Target in Duchenne Muscular Dystrophy

“…For these reasons, as well considering the protective effects observed after the proper stimulation of CB2 receptor, ECS has been proposed as a novel target for cancer, autoimmune, and inflammatory diseases. [ 18 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Iron metabolism alteration delineated the inflammatory status; in particular, a high concentration of pro-inflammatory cytokines (such IL-6) could cause an increase in hepcidin levels that is responsible for intracellular iron accumulation, since it induces the degradation of ferroportin-1 (FPN-1).…”

Emerging Roles of the Iron Chelators in Inflammation

“…Interestingly, it has been demonstrated that lysosomal iron chelation in respiratory epithelial cells avoids lysosomal damage and, consequently, cell death [ 30 ]. An alteration of iron metabolism is reported in Inflammatory Bowel Diseases (IBD), Crohn’s disease (CD), ulcerative colitis (UC), which are chronic inflammatory disorders of the gastrointestinal tract [ 31 ]. It has been revealed that iron accumulation alters gut microbial homoeostasis, worsening intestinal inflammation both in a murine model and in a DSS-induced colitis rat model [ 32 ].…”

“…In particular, high levels of pro-inflammatory cytokines in CD and UC alter bone metabolism inducing bone resorption by determining an increase of the ratio of receptor activator of NF-κB ligand (RANK-L)/Osteoprotegerin (OPG) [ 31 , 43 ]. It has been demonstrated that an alteration of iron metabolism is involved in IBD pathogenesis, with an accumulation of intracellular iron and a reduction of circulating iron [ 31 , 44 ]. The dysregulation of iron metabolism in IBD depends on the overactivation and production of hepcidin, derived by the increased levels of inflammatory state in IBD and, in particular, by high concentration of IL-6 [ 31 , 35 , 39 ].…”

“…It has been demonstrated that an alteration of iron metabolism is involved in IBD pathogenesis, with an accumulation of intracellular iron and a reduction of circulating iron [31,44]. The dysregulation of iron metabolism in IBD depends on the overactivation and production of hepcidin, derived by the increased levels of inflammatory state in IBD and, in particular, by high concentration of IL-6 [31,35,39]. Also in celiac disease, an autoimmune disorder, an alteration of iron metabolism caused by its impaired inflammatory state is reported [45].…”

“…Interestingly, it has been reported that iron accumulation in macrophages is responsible for an excessive stimulation of pro-inflammatory macrophages in chronic venous disease (CVD) IBD chronic inflammation is also responsible for the onset of osteoporosis (OP) in these patients. In particular, high levels of pro-inflammatory cytokines in CD and UC alter bone metabolism inducing bone resorption by determining an increase of the ratio of receptor activator of NF-κB ligand (RANK-L)/Osteoprotegerin (OPG) [31,43]. It has been demonstrated that an alteration of iron metabolism is involved in IBD pathogenesis, with an accumulation of intracellular iron and a reduction of circulating iron [31,44].…”