Effects of recombinant Irisin on the musculoskeletal system of hind-limb suspended mice

We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass, driving positive effects on cortical mineral density and geometry in vivo (1). Here we demonstrated that r-Irisin treatment prevents bone loss in hind-limb suspended mice when administered during suspension and recovers bone mass when mice were injected after a suspension period (4 weeks) during which they developed bone loss. Micro computed tomography of femurs showed that r-Irisin treatment positively affected both cortical and trabecular bone. As expected, unloaded mice treated with vehicle displayed a remarkable decrease of cortical and trabecular bone mineral density (BMD), whereas in Irisin-treated unloaded mice no loss of BMD was observed with respect to control mice kept under normal loading. Likewise, by treating mice after they already developed disuse-induced bone loss, r-Irisin was able to restore the damaged mineral component. Furthermore, trabecular bone volume fraction (BV/TV), which dramatically decreased in unloaded mice, was prevented by r-Irisin therapy. In particular, r-Irisin treatment preserved the number of trabeculae (Tb.N) and the fractal dimension, an index of optimal micro-architectural complexity of trabecular bone.We also showed that r-Irisin treatment protects muscle mass suffering from atrophy during unloading. Thus, unloaded mice treated with vehicle displayed a severe loss of muscle mass, as confirmed by ~ 60% decline of vastus lateralis weight and ~33% decrease of fiber cross-sectional area. Conversely, Irisin-treated unloaded mice showed no loss of muscle weight and similar fiber cross-sectional area to control mice. Our data reveal for the first time that r-Irisin treatment prevents and retrieves disuse-induced bone loss and muscle atrophy. These findings may lead to develop an Irisin-based therapy for the prevention and treatment of osteoporosis and sarcopenia in all patients who cannot perform physical activity, as occurs during aging and immobility, and it could also represent a countermeasure for astronauts exposed to microgravity during space flight missions.This work was supported in part by ERISTO grant (to M.G.), by MIUR grant ex60% (to M.G.) and by SIOMMMS grant (to G.C.)

Treatment with r-irisin prevents and recovers disuse-induced bone loss and muscle atrophy

Irisin is a hormone-like myokine secreted from skeletal muscle in response to exercise. We previously showed that treatment with recombinant Irisin (r-Irisin) in healthy mice improved cortical bone mass and geometry, supporting the idea that Irisin recapitulates some of the most important benefits of physical exercise on the skeleton and plays protective role on bone health (1). Here we show that treatment with r-Irisin prevented bone loss in hind-limb suspended mice when administered during suspension and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks. MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented the dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin inhibited muscle mass decline during unloading, keeping proper fiber cross-sectional area. Notably, the decrease in myosin type II expression (MyHC II) in vastus lateralis of unloaded mice treated with r-Irisin was completely prevented. Our data reveal that r-Irisin treatment protects from disuse induced bone loss and muscle atrophy in mice. If these results will translate to humans, they may support a promising clinical strategy for the prevention and treatment of both osteoporosis and sarcopenia, particularly applicable to those patients who cannot perform physical activity, as occurs during aging, immobility and microgravity during space flight missions

LIGHT/TNFSF14 affects basal bone remodeling

LIGHT (TNFSF14), expressed by different cells of the immune system, binds two trans-membrane receptors: HVEM and LTβR. It is over-expressed in erosive rheumatoid arthritis and lytic myeloma-bone disease and controversial data have been published on its role in osteoclast (OC) formation in vitro. Here, we investigated the role of LIGHT on in vitro murine osteoclastogenesis model and bone phenotype in LIGHT-/- mice. Firstly, we showed that murine macrophages stimulated with LIGHT alone did not differentiate into OCs. Interestingly, the presence of LIGHT and sub-optimal RANKL concentration displayed synergic effects on OC formation through the early and sustained activation of Akt, NFκB and JNK pathways. Secondly, by microCT we found that the femurs of LIGHT-KO mice exhibited a 30% (

Irisin serum levels are positively correlated with bone mineral status in a population of healthy children

Background: Irisin is a myokine secreted by skeletal muscle during physical activity. Irisin treatment increased cortical bone mineral density (BMD) in young healthy mice and restored bone and muscle mass loss in a mouse model of disuse-induced osteoporosis and muscular atrophy. In humans, Irisin was positively correlated with BMD in young athletes. Considering that the bone mass reached during childhood is one of the most important determinants of lifelong skeletal health, we sought to determine if Irisin levels were correlated with bone mineral status in children. Methods: Irisin and bone metabolic markers were quantified in sera and bone mineral status was evaluated by quantitative ultrasound in a population of 34 healthy children (9.82 ± 3.2 years). Results: We found that Irisin levels were positively correlated with the amplitude-dependent speed of sound Z-score (r = 0.305; p < 0.001), bone transmission time Z-score (r = 0.375; p < 0.001) and osteocalcin (r = 0.370; p < 0.001), and negatively with Dickkopf WNT Signaling Pathway Inhibitor 1 (r = −0.274; p < 0.001). Conclusion: In a regression analysis model, Irisin was one of the determinants of bone mineral status to a greater extent than bone alkaline phosphatase and parathyroid hormone, indicating that Irisin might be considered as one of the bone formation markers during childhood

LIGHT/TNFSF14 as a new biomarker of bone disease in multiple myeloma patients experiencing therapeutic regimens

We have previously shown that through the production of high LIGHT levels, immune cells contribute to both osteoclastogenesis and bone destruction in Multiple Myeloma (MM)-related bone disease. With the aim of further exploring the mechanisms underlying the development of MM-related bone disease, here we focused on a possible role of LIGHT in MM patients with active bone disease despite the treatment received. We detected LIGHT over-expression by circulating CD14+ monocytes from MM patients still showing active bone disease, despite the treatment. In addition, we found over-expression of receptor activator of nuclear factor kappa-B ligand (RANKL), whose pro-osteoclastogenic role is well-known, in T-lymphocytes isolated from the same patients. Although the percentages of circulating osteoclast progenitors, CD14+CD16+ monocytes, were higher in all the MM patients than in the controls spontaneous osteoclastogenesis occurred only in the cultures derived from PBMCs of MM patients with unresponsive bone disease. Of note, in the same cultures osteoclastogenesis was partially or completely inhibited, in a dose-dependent manner, by the addition of RANK-Fc or anti-LIGHT neutralizing antibody, demonstrating the contribution of both LIGHT and RANKL to the enhanced osteoclast formation observed. In addition, high serum levels of TRAP5b and CTX, the two markers of osteoclast activity, were detected in MM patients with bone disease not responsive to treatment. In conclusion, our study indicates a prominent role of LIGHT in the crosstalk among osteoclasts and immune cells, co-involved together with RANKL in the pathophysiological mechanisms leading to MM-related bone disease. This TNF superfamily member may thus be a possible new therapeutic target in MM-related bone disease

Sclerostin stimulates angiogenesis in human endothelial cells

Sclerostin, negative regulator of bone formation, has been originally known as an osteocyte product. Recently, it has been also detected in hypertrophic chondrocytes, distinctive cells of avascular cartilage which is invaded by capillaries and then replaced by vascularized bone. Thus, we hypothesized that sclerostin, in addition to its role already known, may exert an angiogenic activity. We first proved that sclerostin increased the proliferation of human umbilical vein endothelial cells (HUVECs), and next, by using the chicken chorioallantoic membrane (CAM) in vivo assay, we demonstrated that it exerts an angiogenic activity similar to that of vascular endothelial growth factor (VEGF). This last finding was reinforced by several in vitro approaches. Indeed, we showed that sclerostin induced the formation of a network of anastomosing tubules, a significant increase in the percentage of tubule number, total tubule length and number of junctions, as well as the ability of sclerostin-stimulated HUVECs to organize capillary-like structures and closed-meshes similar to VEGF. The angiogenic response elicited by the protein may be due to the binding to its receptor, LRP6, which is highly expressed at mRNA and protein levels by sclerostin treated HUVECs and through the production of two well-known pro-angiogenic cytokines, VEGF and placental growth factor (PlGF). Finally, we demonstrated that sclerostin was also responsible for the recruitment of osteoclasts and their circulating monocyte progenitors. Overall, these findings showed for the first time the new angiogenic in vitro role of sclerostin which could be also considered as a novel molecule in angiogenesis-osteogenesis coupling

Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice

We previously showed that Irisin, a myokine released from skeletal muscle after physical exercise, plays a central role in the control of bone mass. Here we report that treatment with recombinant Irisin prevented bone loss in hind-limb suspended mice when administered during suspension (preventive protocol) and induced recovery of bone mass when mice were injected after bone loss due to a suspension period of 4 weeks (curative protocol). MicroCT analysis of femurs showed that r-Irisin preserved both cortical and trabecular bone mineral density, and prevented a dramatic decrease of the trabecular bone volume fraction. Moreover, r-Irisin protected against muscle mass decline in the hind-limb suspended mice, and maintained the fiber cross-sectional area. Notably, the decrease of myosin type II expression in unloaded mice was completely prevented by r-Irisin administration. Our data reveal for the first time that Irisin retrieves disuse-induced bone loss and muscle atrophy. These findings may lead to development of an Irisin-based therapy for elderly immobile osteoporotic and physically disable patients, and might represent a countermeasure for astronauts subjected to microgravity-induced bone and muscle losses

Hypersensitivity reactions to non beta-lactam antimicrobial agents, a statement of the WAO special committee on drug allergy

Antibiotics are used extensively in the treatment of various infections. Consequently, they can be considered among the most important agents involved in adverse reactions to drugs, including both allergic and non-allergic drug hypersensitivity [J Allergy Clin Immunol 113:832-836, 2004]. Most studies published to date deal mainly with reactions to the beta-lactam group, and information on hypersensitivity to each of the other antimicrobial agents is scarce. The present document has been produced by the Special Committee on Drug Allergy of the World Allergy Organization to present the most relevant information on the incidence, clinical manifestations, diagnosis, possible mechanisms, and management of hypersensitivity reactions to non beta-lactam antimicrobials for use by practitioners worldwide