Irisin prevents trabecular bone damage and tumor invasion in a mouse model of multiple myeloma.

Bone disease associated with multiple myeloma (MM) is characterized by osteolytic lesions and pathological fractures, which remain a therapeutic priority despite new drugs improving MM patient survival. Antiresorptive molecules represent the main option for the treatment of MM-associated bone disease (MMBD), whereas osteoanabolic molecules are under investigation. Among these latter, we here focused on the myokine irisin, which is able to enhance bone mass in healthy mice, prevent bone loss in osteoporotic mouse models, and accelerate fracture healing in mice. Therefore, we investigated irisin effect on MMBD in a mouse model of MM induced by intratibial injection of myeloma cells followed by weekly administration of 100 µg/kg of recombinant irisin for 5 wk. By micro-Ct analysis, we demonstrated that irisin improves MM-induced trabecular bone damage by partially preventing the reduction of femur Trabecular Bone Volume/Total Volume (P = .0028), Trabecular Number (P = .0076), Trabecular Fractal Dimension (P = .0044), and increasing Trabecular Separation (P = .0003) in MM mice. In cortical bone, irisin downregulates the expression of Sclerostin, a bone formation inhibitor, and RankL, a pro-osteoclastogenic molecule, while in BM it upregulates Opg, an anti-osteoclastogenic cytokine. We found that in the BM tibia of irisin-treated MM mice, the percentage of MM cells displays a reduction trend, while in the femur it decreases significantly. This is in line with the in vitro reduction of myeloma cell viability after 48 h of irisin stimulation at both 200 and 500 ng/mL and, after 72 h already at 100 ng/mL rec-irisin. These results could be due to irisin ability to downregulate the expression of Notch 3, which is important for cell-to-cell communication in the tumor niche, and Cyclin D1, supporting an inhibitory effect of irisin on MM cell proliferation. Overall, our findings suggest that irisin could be a new promising strategy to counteract MMBD and tumor burden in one shot.

Salivary exosomal microRNA profile as biomonitoring tool for diagnosis and prognosis of patients with head and neck squamous cell carcinoma: a systematic review.

OBJECTIVE: Exosomes are extracellular vesicles found in saliva and other body fluids. These vesicles range in size from 30 to 150 nm and play a crucial role in intercellular communication, transporting different biomolecules, actively targeting cells. These vesicles regulate both physiological and pathological processes within recipient cells. MicroRNAs (miRs) are transported within exosomes and are delivered to target cells where they influence signaling pathways, taking on a crucial regulatory role in oncogenesis; for example, they are implicated in progression and infiltration of various cancers, such as head and neck squamous cell carcinoma (HNSCC). MATERIAL AND METHODS: A systematic literature search based on specific keywords, according to the PRISMA guidelines, was carried out on PubMed, Web of Science, Scopus, and Google Scholar. Only original articles were selected during this review. The risk of bias was assessed by QUADAS-2. RESULTS: At the end of the selection process 9 articles were included. In these studies, 41 miRs showed differential expression between healthy subjects and patient with HNSCC. The techniques varied among studies for the extraction and analysis of exosomal miRs. We presented also salivary exosomal miRs pathways, to give insights about pathogenetic mechanisms. CONCLUSIONS: Exosomal microRNA are promising biomarkers for HNSCC detection. MiR-10b-5p, miR-486-5p, miR-24-3p, miR-412-3p, and miR-512-3p are the most promising markers applicable to diagnostics, while miR-1307-5p and miR-519c-3p resulted overexpressed and correlated to worse survival outcomes.

Possible uses of Hunter-Schreger bands of dental enamel for automated personal identification.

BACKGROUND: Hunter-Schreger bands (HSB) are optical phenomena observed on tooth surfaces under polarized light, resulting from the intersection of enamel prisms. Anthropological studies demonstrate the prevalence of HSB in large mammals, contributing to enamel resistance. Historically, John Hunter and Schreger depicted HSB in dental literature. In dentistry, HSB play a role in non-carious cervical lesions (NCCL) and internal dental perikymata, suggesting their potential for personal identification. Personal identification, crucial in both daily and professional life, involves biometric characteristics, such as fingerprints or facial recognition. The need for non-invasive, rapid, and user-friendly methods has prompted the exploration of using HSB dental images for personal identification. The review aimed to consolidate studies employing HSB for personal identification. METHODS: The scoping review was carried out strictly following the PRISMA-ScR checklist; the search was carried out on tree databases (PubMed, Scopus, Science Direct,) and a register (Cochrane library). RESULTS: The research produced a number of bibliographic sources totaling 410. With the removal of duplicates, 334 were obtained; potentially eligible articles amounted to 14, of which only 4 fully complied with the criteria of eligibility. CONCLUSIONS: From the data in the literature, we can assert that HSB could be used in personal identification, as they are characteristics that are difficult to change and easily detectable.

Short-Term Irisin Treatment Enhanced Neurotrophin Expression Differently in the Hippocampus and the Prefrontal Cortex of Young Mice.

As a result of physical exercise, muscle releases multiple exerkines, such as "irisin", which is thought to induce pro-cognitive and antidepressant effects. We recently demonstrated in young healthy mice the mitigation of depressive behaviors induced by consecutive 5 day irisin administration. To understand which molecular mechanisms might be involved in such effect, we here studied, in a group of mice previously submitted to a behavioral test of depression, the gene expression of neurotrophins and cytokines in the hippocampus and prefrontal cortex (PFC), two brain areas frequently investigated in the depression pathogenesis. We found significantly increased mRNA levels of nerve growth factor (NGF) and fibroblast growth factor 2 (FGF-2) in the hippocampus and brain-derived growth factor (BDNF) in the PFC. We did not detect a difference in the mRNA levels of interleukin 6 (IL-6) and IL-1ß in both brain regions. Except for BDNF in the PFC, two-way ANOVA analysis did not reveal sex differences in the expression of the tested genes. Overall, our data evidenced a site-specific cerebral modulation of neurotrophins induced by irisin treatment in the hippocampus and the PFC, contributing to the search for new antidepressant treatments targeted at single depressive events with short-term protocols.

Irisin Protects against Loss of Trabecular Bone Mass and Strength in Adult Ovariectomized Mice by Stimulating Osteoblast Activity.

Irisin is a peptide secreted by skeletal muscle that plays a major role in bone metabolism. Experiments in mouse models have shown that administration of recombinant irisin prevents disuse-induced bone loss. In this study, we aimed to evaluate the effects of irisin treatment for the prevention of bone loss in the ovariectomized (Ovx) mouse, the animal model commonly used to investigate osteoporosis caused by estrogen deficiency. Micro-Ct analysis conducted on Sham mice (Sham-veh) and Ovx mice treated with vehicle (Ovx-veh) or recombinant irisin (Ovx-irisn) showed bone volume fraction (BV/TV) decreases in femurs (Ovx-veh 1.39± 0.71 vs. Sham-veh 2.84 ± 1.23; p = 0.02) and tibia at both proximal condyles (Ovx-veh 1.97 ± 0.68 vs. Sham-veh 3.48 ± 1.26; p = 0.03) and the subchondral plate (Ovx-veh 6.33 ± 0.36 vs. Sham-veh 8.18 ± 0.41; p = 0.01), which were prevented by treatment with a weekly dose of irisin for 4 weeks. Moreover, histological analysis of trabecular bone showed that irisin increased the number of active osteoblasts per bone perimeter (Ovx-irisin 32.3 ± 3.9 vs. Ovx-veh 23.5 ± 3.6; p = 0.01), while decreasing osteoclasts (Ovx-irisin 7.6 ± 2.4 vs. Ovx-veh 12.9 ± 3.04; p = 0.05). The possible mechanism by which irisin enhances osteoblast activity in Ovx mice is upregulation of the transcription factor Atf4, one of the key markers of osteoblast differentiation, and osteoprotegerin, thereby inhibiting osteoclast formation.

Once-Daily Subcutaneous Irisin Administration Mitigates Depression- and Anxiety-like Behavior in Young Mice.

Major depression is one of the most common psychiatric disorders worldwide, usually associated with anxiety. The multi-etiological nature of depression has increased the search for new antidepressant molecules, including irisin, for which, in a previous study, we tested its effect in young mice when administered intraperitoneally in a long-term intermittent manner. Here, we evaluated the effect of subcutaneous short-term irisin administration (100 µg/Kg/day/5 days) in male and female mice subjected to behavioral paradigms: Tail Suspension Test (TST), Forced Swim Test (FST), Elevated Plus Maze (EPM), and Y Maze (YM). Moreover, a qRT-PCR assay was performed to analyze the impact of irisin treatment on Pgc-1α/FNDC5 expression in the brain. A significant reduction in immobility time in TST and FST was observed in irisin-treated mice. Furthermore, irisin treatment significantly increased the number of entries and time spent in open arms, demonstrating its anxiolytic effect. Memory-enhancing effects were not reported in YM. Interestingly, no gender differences were observed in all behavioral tests. Overall, these results suggest that short-term subcutaneous irisin administration can exert an antidepressant and anxiolytic role, probably due to the activation of the Pgc-1α/FNDC5 system in the brain. Further investigation could lead to the identification of irisin as a new agent for the treatment of psychiatric disorders.

Vitamin D Increases Irisin Serum Levels and the Expression of Its Precursor in Skeletal Muscle.

Irisin is a myokine synthesized by skeletal muscle, which performs key actions on whole-body metabolism. Previous studies have hypothesized a relationship between irisin and vitamin D, but the pathway has not been thoroughly investigated. The purpose of the study was to evaluate whether vitamin D supplementation affected irisin serum levels in a cohort of 19 postmenopausal women with primary hyperparathyroidism (PHPT) treated with cholecalciferol for six months. In parallel, to understand the possible link between vitamin D and irisin, we analyzed the expression of the irisin precursor, Fndc5, in the C2C12 myoblast cell line treated with a biologically active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Our results demonstrate that vitamin D supplementation resulted in a significant increase in irisin serum levels (p = 0.031) in PHPT patients. In vitro, we show that vitamin D treatment on myoblasts enhanced Fndc5 mRNA after 48 h (p = 0.013), while it increased mRNAs of sirtuin 1 (Sirt1) (p = 0.041) and peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1α) (p = 0.017) over a shorter time course. Overall, our data suggest that vitamin-D-induced modulation of Fndc5/irisin occurs through up-regulation of Sirt1, which together with Pgc1α, is an important regulator of numerous metabolic processes in skeletal muscle.

Irisin Modulates Inflammatory, Angiogenic, and Osteogenic Factors during Fracture Healing.

Bone fractures are a widespread clinical event due to accidental falls and trauma or bone fragility; they also occur in association with various diseases and are common with aging. In the search for new therapeutic strategies, a crucial link between irisin and bone fractures has recently emerged. To explore this issue, we subjected 8-week-old C57BL/6 male mice to tibial fracture, and then we treated them with intra-peritoneal injection of r-Irisin (100 µg/kg/weekly) or vehicle as control. At day 10 post fracture, histological analysis showed a significant reduced expression of inflammatory cytokines as tumor necrosis factor-alpha (TNFα) (p = 0.004) and macrophage inflammatory protein-alpha (MIP-1α) (p = 0.015) in the cartilaginous callus of irisin-treated mice compared to controls, supporting irisin's anti-inflammatory role. We also found increased expressions of the pro-angiogenic molecule vascular endothelial growth factor (VEGF) (p = 0.002) and the metalloproteinase MMP-13 (p = 0.0006) in the irisin-treated mice compared to the vehicle ones, suggesting a myokine involvement in angiogenesis and cartilage matrix degradation processes. Moreover, the bone morphogenetic protein (BMP2) expression was also upregulated (p = 0.002). Taken together, our findings suggest that irisin can contribute to fracture repair by reducing inflammation and promoting vessel invasion, matrix degradation, and bone formation, supporting its possible role as a novel molecule for fracture treatment.

Time-dependent unloading effects on muscle and bone and involvement of FNDC5/irisin axis.

The identification of biomarkers and countermeasures to prevent the adverse effects on the musculoskeletal system caused by the absence of mechanical loading is the main goal of space biomedical research studies. In this study, we analyzed over 4 weeks of unloading, the modulation in the expression of key proteins in Vastus lateralis, Gastrocnemius and cortical bone in parallel with the modulation of irisin serum levels and its precursor FNDC5 in skeletal muscle of hind limb unloaded (HU) mice. Here we report that Atrogin-1 was up-regulated as early as 1- and 2-week of unloading, whereas Murf-1 at 2- and 3-weeks, along with a marked modulation in the expression of myosin heavy chain isoforms during unloading. Since HU mice showed reduced irisin serum levels at 4-weeks, as well as FNDC5 decrease at 3- and 4-weeks, we treated HU mice with recombinant irisin for 4 weeks, showing that unloading-dependent decline of myosin heavy chain isoforms, MyHCIIα and MyHCIIx, and the anti-apoptotic factor Bcl2, were prevented. In parallel, irisin treatment inhibited the increase of the senescence marker p53, and the pro-apoptotic factor Bax. Overall, these results suggest that the myokine irisin could be a possible therapy to counteract the musculoskeletal impairment caused by unloading.

Impact of 10-day bed rest on serum levels of irisin and markers of musculoskeletal metabolism.

The bed rest (BR) is a ground-based model to simulate microgravity mimicking skeletal-muscle alterations as in spaceflight. Molecular coupling between bone and muscle might be involved in physiological and pathological conditions. Thus, the new myokine irisin and bone-muscle turnover markers have been studied during and after 10 days of BR. Ten young male individuals were subjected to 10 days of horizontal BR. Serum concentrations of irisin, myostatin, sclerostin, and haptoglobin were assessed, and muscle tissue gene expression on vastus lateralis biopsies was determined. During 10-days BR, we observed no significant fluctuation levels of irisin, myostatin, and sclerostin. Two days after BR (R+2), irisin serum levels significantly decreased while myostatin, sclerostin, and haptoglobin were significantly increased compared with BR0. Gene expression of myokines, inflammatory molecules, transcription factors, and markers of muscle atrophy and senescence on muscle biopsies were not altered, suggesting that muscle metabolism of young, healthy subjects is able to adapt to the hypomobility condition during 10-day BR. However, when subjects were divided according to irisin serum levels at BR9, muscle ring finger-1 mRNA expression was significantly lower in subjects with higher irisin serum levels, suggesting that this myokine may prevent the triggering of muscle atrophy. Moreover, the negative correlation between p21 mRNA and irisin at BR9 indicated a possible inhibitory effect of the myokine on the senescence marker. In conclusion, irisin could be a prognostic marker of hypomobility-induced muscle atrophy, and its serum levels could protect against muscle deterioration by preventing and/or delaying the expression of atrophy and senescence cellular markers.

Circulating Irisin Levels in Patients with Chronic Plaque Psoriasis.

Irisin is an adipo-myokine, mainly synthetized in skeletal muscles and adipose tissues, that is involved in multiple processes. Only a few studies have evaluated serum irisin in psoriatic patients. This study aims to analyze serum irisin levels in patients with chronic plaque psoriasis, to compare them with values in controls, and to assess whether concentration of circulating irisin correlates with the severity of psoriasis, calculated by means of Psoriasis Area and Severity Index (PASI). We enrolled 46 patients with chronic plaque psoriasis; the control group included 46 sex- and age-matched subjects without any skin or systemic diseases. Serum irisin levels were measured by competitive enzyme linked immunosorbent assay. Our results showed a non-significant increase in serum irisin concentration in psoriatic patients compared to controls. A negative non-linear correlation between PASI and irisin levels was detected in psoriatic patients. Indeed, dividing patients according to psoriasis severity, the negative association between irisin and PASI was stronger in patients with mild psoriasis than in patients with higher PASI scores. Several control variables we tested showed no significant impact on serum irisin. However, erythrocyte sedimentation rate in the normal range was associated with significantly higher irisin levels in psoriatic patients. In conclusion, although irisin levels were not significantly different between controls and psoriatic patients, irisin was found to be negatively associated with psoriasis severity, especially in subjects with low PASI scores; however, further studies are needed to clarify the role of irisin in subjects with psoriasis.

Antidepressant Effect of Intermittent Long-Term Systemic Administration of Irisin in Mice.

Depression is a psychiatric disorder increasingly diffused worldwide. Evidence suggests that irisin, a myokine secreted by contracting muscle, mediates beneficial effects on several targets, including the brain. Here, the potential antidepressant properties of long-term intermittent systemic irisin administration (100 µg/kg/weekly for 1 month) were evaluated in mice by the Tail Suspension Test (TST), Forced Swim Test (FST), and Open Field Test (OFT). Furthermore, to deepen the molecular pathways underlying irisin treatment, the expression of irisin precursor, neurotrophic/growth factors, and cytokines was analyzed. Irisin treatment significantly decreased the immobility time in the TST and FST, suggesting an antidepressant effect. Additionally, irisin seemed to display an anxiolytic-like effect increasing the time spent in the OFT arena center. These findings were probably due to the modulation of endogenous brain factors as the gene expression of some neurotrophins, such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF-1), was upregulated only in irisin-treated mouse brain. Moreover, irisin modulated the expression of some cytokines (IL-1ß, IL-4, IL-6, and IL-10). To the best of our knowledge, this is the first study demonstrating that the irisin antidepressant effect may be observed even with a systemic administration in mice. This could pave the way toward intriguing preclinical research in humans.

Systemic Administration of Recombinant Irisin Accelerates Fracture Healing in Mice.

To date, pharmacological strategies designed to accelerate bone fracture healing are lacking. We subjected 8-week-old C57BL/6 male mice to closed, transverse, mid-diaphyseal tibial fractures and treated them with intraperitoneal injection of a vehicle or r-irisin (100 µg/kg/weekly) immediately following fracture for 10 days or 28 days. Histological analysis of the cartilaginous callus at 10 days showed a threefold increase in Collagen Type X (p = 0.0012) and a reduced content of proteoglycans (40%; p = 0.0018). Osteoclast count within the callus showed a 2.4-fold increase compared with untreated mice (p = 0.026), indicating a more advanced stage of endochondral ossification of the callus during the early stage of fracture repair. Further evidence that irisin induced the transition of cartilage callus into bony callus was provided by a twofold reduction in the expression of SOX9 (p = 0.0058) and a 2.2-fold increase in RUNX2 (p = 0.0137). Twenty-eight days post-fracture, microCT analyses showed that total callus volume and bone volume were increased by 68% (p = 0.0003) and 67% (p = 0.0093), respectively, and bone mineral content was 74% higher (p = 0.0012) in irisin-treated mice than in controls. Our findings suggest that irisin promotes bone formation in the bony callus and accelerates the fracture repair process, suggesting a possible use as a novel pharmacologic modulator of fracture healing.

Irisin Correlates Positively With BMD in a Cohort of Older Adult Patients and Downregulates the Senescent Marker p21 in Osteoblasts.

Irisin is a myokine produced by skeletal muscle during exercise in both mice and humans. We previously showed that irisin treatment ameliorates immobility-induced osteoporosis and muscular atrophy in mice. Data in humans showed a positive association between irisin and bone mineral density (BMD) in athletes and a population of healthy children. However, the role of this myokine regarding the state of muscle and bone in the same population remained to be determined. For this purpose, 62 patients (age 68.71 ± 12.31 years) undergoing total hip or knee replacement were recruited. Our results showed that irisin serum levels negatively correlated with age (R = -0.515; p = .000018) and positively correlated with femoral BMD (R = 0.619; p = .001) and vertebral BMD (R = 0.201; p = .0001). Irisin was also positively associated with Fndc5 mRNA in muscle biopsies (R = 0.248; p = .016), as well as with Osteocalcin (Ocn) mRNA in bone biopsies (R = 0.708; p = .006). In skeletal muscle, FNDC5 positive fibers positively correlate with BMD of total femur (R = 0.765; p = .0014) and BMD of femoral neck (R = 0.575; p = .031), Interestingly, by analyzing patients divided by their T-score, we found lower irisin levels (p = .0011) in patients with osteopenia/osteoporosis (OP) compared to healthy controls matched for age and sex. By analyzing the senescence marker p21, we found a significant increase of its mRNA expression in the bone biopsies of OP patients compared to control ones. Therefore, we investigated in vitro whether rec-irisin had a direct effect on this senescence marker, showing that p21 mRNA expression was significantly downregulated in osteoblasts by the treatment with irisin. Overall, these results indicate that higher irisin levels are associated with a lower rate of age-related osteoporosis and that irisin could be effective in delaying the osteoblast aging process, suggesting a potential senolytic action of this myokine. © 2020 American Society for Bone and Mineral Research (ASBMR).

LIGHT/TNFSF14 Promotes Osteolytic Bone Metastases in Non-small Cell Lung Cancer Patients.

Tumor necrosis factor superfamily member 14 (TNFSF14), LIGHT, is a component of the cytokine network that regulates innate and adaptive immune responses, which promote homeostasis of lymphoid organs, liver, and bone. Metastatic tumors often disrupt the tissue microenvironment, thus altering the homeostasis of the invaded organ; however, the underlying mechanisms required further studies. We investigated the role of LIGHT in osteolytic bone disease induced by metastatic non-small cell lung cancer (NSCLC). Patients diagnosed with NSCLC bone metastasis show significantly higher levels of LIGHT expressed in monocytes compared with non-bone metastatic tumors and healthy controls. Serum LIGHT levels were also higher in patients with bone metastases than in controls, suggesting a role for LIGHT in stimulating osteoclast precursors. In bone metastatic patients, we also detected increased RNA expression and serum RANKL levels, thus by adding anti-LIGHT or RANK-fragment crystallizable region (RANK-Fc) in PBMC cultures, a significant inhibition of osteoclastogenesis was observed. To model this observation in mice, we used the mouse lung cancer cell line LLC-1. After intratibial implantation, wild-type mice showed an increased number of osteoclasts but reduced numbers of osteoblasts and decreased osteoid formation. In contrast, Tnfsf14-/- mice showed no significant bone loss or other changes in bone homeostasis associated with this model. These data indicate LIGHT is a key control mechanism for regulating bone homeostasis during metastatic invasion. Thus, LIGHT may be a novel therapeutic target in osteolytic bone metastases. © 2019 American Society for Bone and Mineral Research.

Irisin Prevents Disuse-Induced Osteocyte Apoptosis.

Previous results showed that intermittently administered irisin improves bone mass in normal mice and prevents the development of disuse-induced osteoporosis and muscular atrophy in hindlimb-suspended mice, a murine model able to mimic the absence of mechanical loading. A recent study showed that irisin increases survival of osteocytes acting through integrin αV/ß5 receptors. To better understand the action of irisin on these cells, we investigated the downstream signaling cascades in osteocyte-like cells (MLO-Y4) treated with recombinant irisin (rec-irisin) in vitro and we analyzed survival of osteocytes and caspase activation in cortical bone of osteoporotic mice treated with rec-irisin in vivo. Our results revealed that rec-irisin activated the MAP kinases Erk1 and Erk2 and increased the expression of the transcription factor Atf4 (2.5-fold, p < .05) through an Erk-dependent pathway in osteocytes. Some key genes expressed by MLO-Y4 cells were modulated by long-term irisin treatment, either continuously administered or given with intermittent short pulses. Interestingly, Sost mRNA was severely downregulated only upon intermittent irisin administration (10-fold, p < .001). Furthermore, rec-irisin upregulated Tfam mRNA (fourfold, p < .05) and Bcl2/Bax ratio (twofold, p < .05) in MLO-Y4 cells. By detecting caspase-9 and caspase-3, we also found that rec-irisin inhibited apoptosis induced by hydrogen peroxide and dexamethasone, respectively. In cortical bone of unloading C57BL6 mice treated with vehicle (unload-veh), irisin prevented disuse-induced reduction of viable osteocytes (+30% versus unload-veh, p < .05) and increase of empty lacunae (+110% versus unload-veh, p < .05), as well as caspase-9 (threefold, p < .05) and caspase-3 (twofold, p < .05) activations. Our findings revealed underlying mechanisms of irisin action on osteocytes, which increases their functions and exerts anti-apoptotic effects, confirming that mechanosensor cells of bone are sensitive to the exercise-mimetic myokine irisin. © 2019 American Society for Bone and Mineral Research.

Irisin and Bone: From Preclinical Studies to the Evaluation of Its Circulating Levels in Different Populations of Human Subjects.

Almost four years after the discovery of the anabolic action of irisin on bone in mice, ample clinical evidence is emerging in support of its additional physiological relevance in human bone. Irisin inversely correlates with sclerostin levels in adults with prediabetes and with vertebral fragility fractures in post-menopausal women. Furthermore, in athletes we observed a positive correlation between irisin and bone mineral density at different anatomical sites. Our group also described a positive association between serum irisin and bone status in healthy children and multivariate regression analysis showed that irisin is a stronger determinant of bone mineral status than bone alkaline phosphatase. In children with type 1 diabetes mellitus, serum irisin concentrations are positively associated with bone quality and with glycemic control following continuous subcutaneous insulin infusion. Additionally, our in vitro studies suggest the existence of a negative interplay between PTH and irisin biology and these results were also supported by the observation that post-menopausal women with primary hyperparathyroidism have lower levels of irisin compared to matched controls. In this review, we will focus on recent findings about circulating level of irisin in different populations of human subjects and its correlation with their bone status.

A Novel Interplay Between Irisin and PTH: From Basic Studies to Clinical Evidence in Hyperparathyroidism.

CONTEXT: Irisin is a hormonelike molecule that is cleaved and secreted by an unknown protease from fibronectin type III domain-containing protein 5 (FNDC5). It ameliorates bone status and muscle atrophy and influences energy homeostasis. PTH exerts several metabolic effects that may interact with the effects of irisin. OBJECTIVES: To test the hypothesis that irisin and PTH mutually affect their biological action, we evaluated FNDC5 mRNA and protein expression in myotubes treated with PTH (1-34) and parathyroid hormone receptor (PTH-r) mRNA expression in osteoblasts treated with r-irisin. To confirm the in vivo impact of PTH on irisin, we compared irisin serum concentrations in postmenopausal women with primary hyperparathyroidism (PHPT) and control subjects. DESIGN AND INTERVENTION: C2C12 myotubes were treated with short-term and continuous 10-10 M teriparatide and MC3T3-E1 osteoblasts with 100 ng/mL r-irisin for 8 hours. In a cross-sectional open-label trial, we enrolled 26 postmenopausal women with PHPT and 31 age-/body mass index (BMI)‒matched control subjects without impairment of calcium/phosphate metabolism. RESULTS: Teriparatide treatment on myotubes significantly downregulated FNDC5 expression by acting through its own receptor, which in turn activated Erk11/2 phosphorylation. r-Irisin led to a 50% downregulation of PTH-r mRNA expression compared with untreated cells (P < 0.001). Irisin was significantly lower in the PHPT group than in age-/BMI-matched controls (4.5 ± 1.1 vs 12 ± 5.2 µg/mL; P < 0.001). No significant correlation between irisin and bone mineral density or PTH was recorded in the PHPT group. CONCLUSION: Preclinical findings suggest the existence of an interplay between PTH and irisin metabolism that seems to be confirmed by the significant reduction of irisin concentration in postmenopausal women with PHPT.

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.