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BACKGROUND Osteoporosis affects millions of postmenopausal women worldwide. Invariant natural killer T cells (iNKT) are important cells for bone homeostasis. The sim of this study was to investigate the contribution of invariant natural killer T cells (iNKT) in the increased receptor activator of the nuclear factor-kappaB ligand (RANKL) pool and bone resorption, a characteristic of patients with osteoporosis. MATERIAL AND METHODS Whole blood was collected from 79 female patients. The dual energy x-absorptiometry scan was performed in all patients, and the T-score was calculated in order to classify our patients according to the World Human Organization (WHO) criteria for diagnosis and classification of osteoporosis. Eleven patients had a T-score -2.5 and were included in the osteoporosis group. We performed alpha-galactosylceramide activation of iNKT cells in vitro. Surface RANKL expression was detected by multicolor flow cytometry in naive and activated lymphocytes. Beta-Crosslaps (ß-CTx) levels were measured in whole blood plasma by ELISA (enzyme-linked immunosorbent assay). RESULTS Although iNKT cells were not clonally expanded in patients with osteoporosis, iNKT cells from osteoporotic patients overexpressed RANKL compared to ND and osteopenic patients. This is a distinctive feature of iNKT cells and is not seen in conventional T-lymphocytes. RANKL expression in iNKT cells was not related to ß-CTx levels in the blood. Finally, iNKT cell activation by the prototypal glycolipid ligand alpha-galactosylceramide increased by 8 times their RANKL expression. CONCLUSIONS In patients with osteoporosis, iNKT cells specifically overexpress RANKL, a cytokine that regulates osteoclast activity. It seems that iNKT cells have a long-standing effect of on the bone physiology, which plays an important role in the bone loss of patients with osteoporosis.

Cardiovascular (CV) disease and osteoporosis (OP) have become increasing challenges in the aging population and even more in patients with inflammatory rheumatic diseases, such as rheumatoid arthritis, spondyloarthropathies, and systemic lupus erythematosus. In this review, we discuss how the epidemiology and pathogenesis of CV events and OP are overlapping. Smoking, diabetes mellitus, physical inactivity as conventional risk factors as well as systemic inflammation are among the modifiable risk factors for both CV events and bone loss. In rheumatic patients, systemic "high-grade" inflammation may be the primary driver of accelerated atherogenesis and bone resorption. In the general population, in which some individuals might have low-grade systemic inflammation, a holistic approach to drug treatment and lifestyle modifications may have beneficial effects on the bone as well as the vasculature. In rheumatic patients with accelerated inflammatory atherosclerosis and bone loss, the rapid and effective suppression of inflammation in a treat-to-target regime, aiming at clinical remission, is necessary to effectively control comorbidities.

Recently, they increasingly began to pay attention to the role of a nonspecific immune-inflammatory vascular response as a link in general pathogenetic mechanisms with a change in the elastic properties of arteries and phenomena of destructive bone changes, which at the subclinical level is of great importance for the prevention of the development of socially significant diseases. A total of 104 patients were examined (mean age 57.45 years), which were divided into three groups. The first group included 39 healthy women, the second group included 30 patients with hypertension and osteopenia, and the third group included 35 women with hypertension and osteoporosis. The analysis of markers of the immune inflammatory response, endothelial dysfunction, hormonal and mineral-vitamin status parameters was conducted against the background of the study of parameters of daily monitoring of arterial pressure, study of parameters of vascular wall stiffness and densitometry to clarify the predictors of cardiovascular and degenerative bone changes in postmenopausal women. A significant increase in the concentration of HF-CRP, the level of homocystemine, IL-8, parathyroid hormone, against the background of a significant decrease in the level of estrogen, progesterone, testosterone, with a persistent tendency to increase in total cholesterol, atherogenic lipid fractions, myeloperoxidase, endothelin-1 and decrease was recorded calcitonin, total and ionized calcium, with a significantly minimal value of vitamin D in the 3rd group of patients. The risks of development and progression of bone destructive changes were calculated using the logistic regression method for the group of AH with osteopenia and osteoporosis. Thus, for patients with hypertension and osteopenia, a significantly significant parameter associated with the risk of developing osteoporosis was an indicator of the velocity of the pulse wave, an increase in the level of which exceeds 12.05 m/s is associated with an increased risk of developing osteoporosis by 3.8 times. Increased levels of pro-inflammatory parameters, IL-6 and 8, TNF-α, HB-SRB, parathyroid hormone and reduced levels of progesterone and IL10, took the most active part in aggravating the degree of available bone tissue destruction. Timely specialized multidirectional study of biochemical and instrumental parameters (in particular, the study of the speed of the pulse wave and densitometry) can be the basis for the development of personalized prevention and treatment tactics for women in order to prevent socially dangerous cardiovascular and bone complications., Competing Interests: The authors declare no conflict of interest.

Glucocorticoids are widely used to treat varieties of allergic and autoimmune diseases, however, long-term application results in glucocorticoid-induced osteoporosis (GIOP). Inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) play important regulatory roles in bone metabolism, but their roles in GIOP remain largely unknown. Osteocytes can modulate the formation and function of both osteoblasts and osteoclasts, directly via gap junctions, or indirectly by transferring molecule signaling. Apoptotic osteocytes release RANKL, HMGB1 and pro-inflammatory cytokines to stimulate osteoclastogenesis. Moreover, osteocytes can secrete FGF23 to regulate bone metabolism. Exposure to high levels of GCs can drive osteocyte apoptosis and influence gap junctions, leading to bone loss. GCs treatment is regarded to produce more FGF23 to inhibit bone mineralization. GCs also disrupt the vascular to decrease osteocyte feasibility and mineral appositional rate, resulting in a decline in bone strength. Apoptotic bodies from osteocytes induced by GCs treatment can enhance production of TNF-α and IL-6. On the other hand, TNF-α and IL-6 show synergistic effects by altering osteocytes signaling towards osteoclasts and osteoblasts. In addition, TNF-α can induce osteocyte apoptosis and attribute to a worsened bone quality in GCs. IL-6 and osteocytes may interact with each other. Therefore, we hypothesize that GCs regulate osteocyteogenesis through TNF-α and IL-6, which are highly expressed around osteocyte undergoing apoptosis. In the present review, we summarized the roles of osteocytes in regulating osteoblasts and osteoclasts. Furthermore, the mechanism of GCs altered relationship between osteocytes and osteoblasts/osteoclasts. In addition, we discussed the roles of TNF-α and IL-6 in GIOP by modulating osteocytes. Lastly, we discussed the possibility of using pro-inflammatory signaling pathway as therapeutic targets to develop drugs for GIOP., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The gut microbiome is now viewed as a tissue that interacts bidirectionally with the gastrointestinal, immune, endocrine and nervous systems, affecting the cellular responses in numerous organs. Evidence is accumulating of gut microbiome involvement in a growing number of pathophysiological processes, many of which are linked to inflammatory responses. More specifically, data acquired over the last decade point to effects of the gut microbiome on bone mass regulation and on the development of bone diseases (such as osteoporosis) and of inflammatory joint diseases characterized by bone loss. Mice lacking a gut microbiome have bone mass alteration that can be reversed by gut recolonization. Changes in the gut microbiome composition have been reported in mice with estrogen-deficiency osteoporosis and have also been found in a few studies in humans. Probiotic therapy decreases bone loss in estrogen-deficient animals. The effect of the gut microbiome on bone tissue involves complex mechanisms including modulation of CD4 + T cell activation, control of osteoclastogenic cytokine production and modifications in hormone levels. This complexity may contribute to explain the discrepancies observed betwwen some studies whose results vary depending on the age, gender, genetic background and treatment duration. Further elucidation of the mechanisms involved is needed. However, the available data hold promise that gut microbiome manipulation may prove of interest in the management of bone diseases., (Copyright © 2018 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Osteoporosis develops with high prevalence in both postmenopausal women and hypogonadal men. Osteoporosis results in significant morbidity, but no cure has been established. Mesenchymal stem cells (MSCs) critically contribute to bone homeostasis and possess potent immunomodulatory/anti-inflammatory capability. Here, we investigated the therapeutic efficacy of using an infusion of MSCs to treat sex hormone-deficient bone loss and its underlying mechanisms. In particular, we compared the impacts of MSC cytotherapy in the two genders with the aim of examining potential gender differences. Using the gonadectomy (GNX) model, we confirmed that the osteoporotic phenotypes were substantially consistent between female and male mice. Importantly, systemic MSC transplantation (MSCT) not only rescued trabecular bone loss in GNX mice but also restored cortical bone mass and bone quality. Unexpectedly, no differences were detected between the genders. Furthermore, MSCT demonstrated an equal efficiency in rectifying the bone remodeling balance in both genders of GNX animals, as proven by the comparable recovery of bone formation and parallel normalization of bone resorption. Mechanistically, using green fluorescent protein (GFP)-based cell-tracing, we demonstrated rapid engraftment but poor inhabitation of donor MSCs in the GNX recipient bone marrow of each gender. Alternatively, MSCT uniformly reduced the CD3 + T-cell population and suppressed the serum levels of inflammatory cytokines in reversing female and male GNX osteoporosis, which was attributed to the ability of the MSC to induce T-cell apoptosis. Immunosuppression in the microenvironment eventually led to functional recovery of endogenous MSCs, which resulted in restored osteogenesis and normalized behavior to modulate osteoclastogenesis. Collectively, these data revealed recipient sexually monomorphic responses to MSC therapy in gonadal steroid deficiency-induced osteoporosis via immunosuppression/anti-inflammation and resident stem cell recovery.

Gut microbiota are involved in the development or prevention of various diseases such as type 2 diabetes, fatty liver, and malignancy such as colorectal cancer, breast cancer and hepatocellular carcinoma. Alzheimer's disease, osteoporosis, sarcopenia, atherosclerotic stroke and cardiovascular disease are major diseases associated with decreased activities of daily living (ADL), especially in elderly people. Recent analyses have revealed the importance of gut microbiota in the control of these diseases. The composition or diversity of these microbiota is different between patients with these conditions and healthy controls, and administration of probiotics or prebiotics has been shown effective in the treatment of these diseases. Gut microbiota may affect distant organs through mechanisms that include regulating the absorption of nutrients and/or the production of microbial metabolites, regulating and interacting with the systemic immune system, and translocating bacteria/bacterial products through disrupted mucosal barriers. Thus, the gut microbiota may be important regulators in the development of diseases that affect ADL. Although adequate exercise and proper diet are important for preventing these diseases, their combination with interventions that manipulate the composition and/or diversity of gut microbiota could be a promising strategy for maintaining health condition and preserving ADL. This review thus summarizes current understanding of the role of gut microbiota in the development or prevention of diseases closely associated with the maintenance of ADL., Competing Interests: Conflict-of-interest statement: No conflict-of interest to declare.

Bone loss in women accelerates during perimenopause, and continues into old age. To-date, there has been little progress made in stratifying for fracture risk in premenopausal and early postmenopausal women. Epidemiologic data suggests that changes in serum FSH could predict decrements in bone mass during peri- and postmenopause. In bone, FSH stimulates osteoclast formation by releasing osteoclastogenic cytokines. Here, we address the evidence for bone loss across the menopausal transition, discuss strategies for detection and treatment of early postmenopausal osteoporosis, and describe the role FSH plays in physiology and likely in pathophysiology of early postmenopausal bone loss., (Copyright © 2018. Published by Elsevier B.V.)

Skeletal homeostasis is dynamically influenced by the immune system. Low density lipoprotein receptor-related protein-5 (LRP5) is a co-receptor of the Wnt signaling pathway, which modulates bone metabolism in humans and mice. Immune disorders can lead to abnormal bone metabolism. It is unclear whether and how LRP5 alters the balance of the immune system to modulate bone homeostasis. In this study, we used primary osteoblast to detect the differentiation of osteoblasts in vitro, the immune cells of spleen and bone marrow of 6-month old LRP5 heterozygote (HZ) and wild-type (WT) mice were analyzed by Flow cytometry. We found that LRP5 +/- could influence the differentiation of osteoblasts by decreasing the mRNA level of Osterix, and increasing the mRNA level of Runx2 and the ratio of receptor activator for nuclear factor-κB ligand/osteoprotegerin (RANKL/OPG). In the LRP5 +/- mice, percentages of NK cells, CD3e + cells, and CD8a + T cells were increased in both spleen and bone marrow, and percentages of CD106 + cells and CD11c + cells were increased in spleen while decreased in bone marrow, conversely, CD62L + cells were decreased in spleen while increased in bone marrow compared to the WT mice. Percentages of CD4 + cells, CD14 + cells, and CD254 + cells were increased in the spleen, and CTLA4 + cells were increased in the bone marrow of the LRP5 +/- mice. The mRNA level of Wnt signaling molecules such as β-catenin, and c-myc were decreased and APC was increased in spleen lymphocytes and bone marrow lymphocytes, and the mRNA level of Wnt3a was decreased in spleen lymphocytes while no change in bone marrow lymphocytes was seen with silencing LRP5 by specific small interfering RNA. In conclusion, heterozygous deletion of the LRP5 gene in mice could alter the profile of the immune cells, influence the balance of immune environment, and modulate bone homeostasis, which might present a potential mechanism to explore the Wnt signaling pathway in the modulation of the immune system.

Post-menopausal osteoporosis is a bone formation disorder induced by estrogen deficiency. Estrogen deficiency facilitates the differentiation and maturation of osteoclasts by activating T lymphocytes. In our previous study, it was demonstrated that estrogen promotes bone marrow mesenchymal stem cell (BMMSC)‑induced osteoclast apoptosis through downregulation of microRNA (miR)‑181a and subsequent Fas ligand (FasL) protein accumulation. In the present study, the regulatory effects of miR‑181a on FasL expression in BMMSCs and the apoptotic effects of BMMSCs on cluster of differentiation (CD)4+T lymphocytes were investigated. An ovariectomized mouse model of osteoporosis (OVX) was established and CD4+T lymphocytes were isolated from the bones of these mice. The results demonstrated that the number of CD4+T lymphocytes was increased in the OVX group compared within the control group, thus suggesting that estrogen deficiency may increase CD4+T lymphocyte number. CD4+T lymphocytes were subsequently co‑cultured with estrogen‑treated BMMSCs, after which it was demonstrated that estrogen significantly promoted the apoptosis of CD4+T lymphocytes. Western blot analysis indicated that estrogen promoted the apoptosis of CD4+T lymphocytes through regulation of FasL expression in BMMSCs in a concentration‑dependent manner. Finally, miR‑181a was transfected into BMMSCs, which were co‑cultured with CD4+T lymphocytes in vitro and in vivo. The results revealed that miR‑181a exerted a negative regulatory effect on BMMSC‑induced CD4+T lymphocyte apoptosis by regulating FasL protein expression in BMMSCs; this maybe a key mechanism underlying the development of estrogen deficiency‑induced osteoporosis.

Atherosclerosis and osteoporosis are epidemiologically linked and oxidation specific epitopes (OSEs), such as phosphocholine (PC) of oxidized phospholipids (PC-OxPL) and malondialdehyde (MDA), are pathogenic in both. The proatherogenic effects of OSEs are opposed by innate immune antibodies. Here we show that high-fat diet (HFD)-induced bone loss is attenuated in mice expressing a single chain variable region fragment of the IgM E06 (E06-scFv) that neutralizes PC-OxPL, by increasing osteoblast number and stimulating bone formation. Similarly, HFD-induced bone loss is attenuated in mice expressing IK17-scFv, which neutralizes MDA. Notably, E06-scFv also increases bone mass in mice fed a normal diet. Moreover, the levels of anti-PC IgM decrease in aged mice. We conclude that OSEs, whether produced chronically or increased by HFD, restrain bone formation, and that diminished defense against OSEs may contribute to age-related bone loss. Anti-OSEs, therefore, may represent a novel therapeutic approach against osteoporosis and atherosclerosis simultaneously.

Osteoporosis can be classified as an inflammatory disease and the crosstalk between the immune system and bone growth should be considered. The effects of bovine lactoferrin on bone by osteoimmunology were investigated in the present study. Ten week old female BALB/c mice were ovariectomized (OVX) and fed for 12 weeks with a control diet or lactoferrin (2, 20 and 100 mg kg-1 d-1). The results showed that following 12 weeks of treatment after surgery, OVX resulted in bone loss, but treatment with lactoferrin preserved bone homeostasis. Lactoferrin significantly improved bone mineral density, and increased the serum levels of alkaline phosphatase, while it decreased the serum levels of tartrate-resistant acid phosphatase. Furthermore, according to micro-computed tomography (micro-CT), the bone volume per tissue volume (BV/TV), trabecular thickness (Tb.Th) and trabecular number (Tb.N) were elevated. The results indicated that the structure model index (SMI) was reduced in the OVX + LF groups. Additionally, lactoferrin enhanced the Max-Load and Max-Stress values of the femur, and increased the content of Ca and P. However, lactoferrin suppressed the RANKL/OPG ratio in OVX mice. Moreover, interferon-γ, interleukin-5 and interleukin-10 were elevated significantly in the OVX + LF groups. Lactoferrin had a positive effect on the bone micro-environment and might be a pleiotropic protein for the prevention and treatment of estrogen-dependent bone loss via the osteoimmunology pathway.

The purpose of this study was to illustrate the effects of zinc oxide nanoparticles (ZnO-NPs) administration on bone turnover and bone resorbing agents in rats and how L-arginine (L-arg) or vitamin E (vit E) co-administrations might affect them. Fasting rats were randomly divided into four groups (n = 10): G1-normal healthy animals; G2-ZnO-NPs-exposed rats (600 mg/kg - 1/day -1 ); G3-ZnO-NPs-exposed rats co-administrated L-arg (200 mg/kg - 1/day -1 ); G4-ZnO-NPs-exposed rats co-administrated vit E (200 mg/kg - 1/day -1 ). The ingredients were orally administered daily. The body weight and food consumption of rats were recorded during the administration period and the experiment continued for three consecutive weeks. The results demonstrated that ZnO-NPs administration induced bone loss in rats as manifested by reduced activity of bone alkaline phosphatase (B-ALP) and increased level of C-terminal peptide type I collagen (CTx). The increase of inflammatory markers, tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) by ZnO-NPs suggests that deleterious effects of ZnO-NPs on bone turnover were, in part, due to inflammation. Confirming to this suggestion, both L-arg and vit E reduced TNF-α and IL-6 levels and consequently decreased bone resorption as indicated by reduced serum CTx level. This study proved that ZnO-NPs can induce bone turnover, which may be reduced by L-arg or vit.E co-administration, partly by anti-inflammatory mechanism.

Aging is associated with the development of osteoporosis, in which cellular senescence in osteoblasts plays a key role. Leukotriene D4 (LTD4), an important cysteinyl leukotriene (cysLT), is a powerful pro-inflammatory mediator formed from arachidonic acid. However, little information regarding the effects of LTD4 on the pathogenesis of osteoporosis has been reported before. In the present study, we defined the physiological roles of LTD4 in cellular senescence in osteoblasts. Our results indicate that LTD4 treatment decreased the expression of SIRT1 in a dose-dependent manner in MC3T3-E1 osteoblastic cells. Additionally, LTD4 significantly increased the expression of p53, p21 and plasminogen activator inhibitor-1 (PAI-1). LTD4 was also found to elevate the activity of β-galactosidase (SA-β-Gal) but to prevent BrdU incorporation. Our results indicate that cysteinyl leukotriene receptor 1 (cysLT1R) could be detected in MC3T3-E1 osteoblastic cells at both the mRNA and protein levels. However, cysLT2R was not expressed in these cells. Interestingly, we found that knockdown of cysLT1R or use of the selective cysLT1R antagonist montelukast abolished the LTD4-induced reduction in SIRT1 and increase in p53, p21, and PAI-1. Notably, knockdown of cysLT1R by transfection with cysLT1R siRNA or treatment with montelukast attenuated the LTD4-induced increase in SA-β-Gal activity. Our study shows for the first time that LTD4 has a significant impact on cellular senescence in osteoblasts., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This article reviews recent advances in the research of the mechanisms of bone loss, as well as clinical features, economic impact and therapeutic implications of osteoporosis and fractures in patients with systemic lupus erythematosus (SLE) as an illustration of bone disease in a complex systemic autoimmune connective tissue disease. Recent studies demonstrated an increased incidence of osteoporosis and peripheral and vertebral fractures in patients with SLE. The aetiology of bone loss in SLE is multifactorial, including clinical osteoporosis risk factors, systemic inflammation, serological factors, metabolic factors, hormonal factors, possibly genetic factors and medication-induced adverse effects. The incidence of symptomatic fractures in patients with SLE is increased 1.2-4.7-fold and age, disease duration, glucocorticoid use, previous cyclophosphamide use, seizures and a prior cerebrovascular event have been identified as important risk factors. Moreover, a high prevalence of morphometric vertebral fractures was demonstrated, while one in three of these patients has normal bone density, which finding points to the multifactorial aetiology of fractures in SLE. The clinical consequences and economic burden of osteoporosis and fractures as glucocorticoid treatment-related adverse events and the high frequency of glucocorticoid therapy underline the importance of reducing glucocorticoid treatment and prescribing steroid-sparing agents. No data on fall risk and its determinants and the relationship with the occurrence of fractures in patients with SLE are currently available. Fall risk might be increased in lupus patients for several reasons. In addition, the recently reported high prevalence (20%) of frailty in SLE patients may contribute to the increased fracture incidence. Therefore, the relationships between fall risk, frailty and fracture occurrence in SLE might be interesting subjects for future studies.

Bone loss is characteristic of the ageing process and a common complication of many autoimmune diseases. Research has highlighted a potential role of autoantibodies in pathologic bone loss. The confounding effects of immunomodulatory drugs make it difficult to establish the contribution of autoantibodies amongst autoimmune disease sufferers. We attempted to examine the relationship between autoantibodies and bone mass in a population of 2812 elderly participants without clinical autoimmune disease. Serum samples were assayed for a panel of autoantibodies (anti-nuclear, extractable nuclear antigen, anti-neutrophil cytoplasmic, thyroid peroxidase, tissue transglutaminase, anti-cardiolipin, rheumatoid factor, and cyclic citrullinated peptide). Bone mass was measured using quantitative ultrasound (QUS) of the calcaneus. The relationship between each autoantibody and bone mass was determined using linear regression models. Anti-nuclear autoantibodies were the most prevalent, positive in approximately 11%, and borderline in roughly 23% of our sample. They were also the only autoantibody observed to be significantly associated with QUS index in the univariate analysis ( n = 1628; r = -0.20; 95% CI: -0.40-0.00; p = 0.046). However, statistical significance was lost after adjustment for various other potential confounders. None of the other autoantibodies was associated with QUS index in either univariate or multivariate analysis. We are limited by the cross-sectional nature of the study and the low prevalence of autoantibodies in our nonclinical sample.

The role of immune system in various bone pathologies, such as osteoporosis, osteoarthritis, and rheumatoid arthritis is now well established. This had led to the emergence of a modern field of systems biology called as osteoimmunology, an integrated research between fields of immunology and bone biology under one umbrella. Osteoporosis is one of the most common inflammatory bone loss condition with more than 200 million individuals affected worldwide. T helper (Th) cells along with various other immune cells are major players involved in bone homeostasis. In the present review, we specifically discuss the role of various defined T lymphocyte subsets (Th cells comprising Th1, Th2, Th9, Th17, Th22, regulatory T cells, follicular helper T cells, natural killer T cells, γδ T cells, and CD8 + T cells) in the pathophysiology of osteoporosis. The study of the specific role of immune system in osteoporosis has now been proposed by our group as "immunoporosis: the immunology of osteoporosis" with special emphasis on the role of various subsets of T lymphocytes. The establishment of this new field had been need of the hour due to the emergence of novel roles of various T cell lymphocytes in accelerated bone loss observed during osteoporosis. Activated T cells either directly or indirectly through the secretion of various cytokines and factors modulate bone health and thereby regulate bone remodeling. Several studies have summarized the role of inflammation in pathogenesis of osteoporosis but very few reports had delineated the precise role of various T cell subsets in the pathobiology of osteoporosis. The present review thus for the first time clearly highlights and summarizes the role of various T lymphocytes in the development and pathophysiology of osteoporosis, giving birth to a new field of biology termed as "immunoporosis". This novel field will thus provide an overview of the nexus between the cellular components of both bone and immune systems, responsible for the observed bone loss in osteoporosis. A molecular insight into the upcoming and novel field of immunoporosis would thus leads to development of innovative approaches for the prevention and treatment of osteoporosis.

Exposed surfaces of mammals are colonized with 100 trillion indigenous bacteria, fungi, and viruses, creating a diverse ecosystem known as the microbiome. The gastrointestinal tract harbors the greatest numbers of these microorganisms, which regulate human nutrition, metabolism, and immune system function. Moreover, the intestinal microbiota contains pro- and anti-inflammatory products that modulate immune responses and may play a role in maintaining gut barrier function. Therefore, the community composition of the microbiota has profound effects on the immune status of the host and impacts the development and/or progression of inflammatory diseases. Accordingly, numerous studies have shown differences in the microbiota of patients with and without a given inflammatory condition. There is now strong evidence that the gut microbiome regulates bone homeostasis in health and disease, and that prebiotic and probiotics protect against bone loss. Herein, the evidence supporting the role of the microbiota and the effects of prebiotic and probiotics will be reviewed., (Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.)

Bone marrow-derived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft- vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-α in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.-Liao, L., Yu, Y., Shao, B., Su, X., Wang, H., Kuang, H., Jing, H., Shuai, Y., Yang, D., Jin, Y. Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.

Probiotics have been consumed by humans for thousands of years because they are beneficial for long-term storage of foods and promote the health of their host. Ingested probiotics reside in the gastrointestinal tract where they have many effects including modifying the microbiota composition, intestinal barrier function, and the immune system which result in systemic benefits to the host, including bone health. Probiotics benefit bone growth, density, and structure under conditions of dysbiosis, intestinal permeability, and inflammation (recognized mediators of bone loss and osteoporosis). It is likely that multiple mechanisms are involved in mediating probiotic signals from the gut to the bone. Studies indicate a role for the microbiota (composition and activity), intestinal barrier function, and immune cells in the signaling process. These mechanisms are not mutually exclusive, but rather, may synergize to provide benefits to the skeletal system of the host and serve as a starting point for investigation. Given that probiotics hold great promise for supporting bone health and are generally regarded as safe, future studies identifying mechanisms are warranted.

During the last 40 years, understanding of bone biology and the pathogenesis of osteoporosis, the most common and impactful bone disease of old age, has improved dramatically thanks to basic and clinical research advances, genetic insights from humans and rodents, and newer imaging technologies. Culprits of osteoporosis are no longer a matter of speculation based on in vitro observations. Instead, they can be identified and dissected at the cellular and molecular level using genetic approaches; and their effect on distinct bone envelopes and anatomic regions can be functionally assessed in vivo. The landscape of pharmacotherapies for osteoporosis has also changed profoundly with the emergence of several potent antiresorptive drugs as well as anabolic agents, displacing estrogen replacement as the treatment of choice. In spite of these major positive developments, the optimal duration of the available therapies and their long-term safety remain matters of conjecture and some concern. Moreover, antiresorptive therapies are used indiscriminately for patients of all ages on the assumption that suppressing remodeling is always beneficial for bone, but rebound remodeling upon their discontinuation suggests otherwise. In this invited perspective, I highlight the latest state of knowledge of bone-intrinsic and extrinsic mechanisms responsible for the development of osteoporosis in both sexes; differences between the mechanisms responsible for the effects of aging and estrogen deficiency; and the role of old osteocytes in the development of cortical porosity. In addition, I highlight advances toward the goal of developing drugs for several degenerative diseases of old age at once, including osteoporosis, by targeting shared mechanisms of aging. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

Diabetes mellitus is a major cause to induce osteoporosis. Though the pathogenesis of osteoporosis progression has been well investigated, its still not fully understood. Recently, cereblon (CRBN) was considered as a negative modulator of adenosine monophosphate-activated protein kinase (AMPK) in vitro and in vivo. Here, we presented results indicating that CRBN could effectively regulate osteoporosis development. In STZ-induced wild type (WT) mice with diabetes, the osteoclasts were highly increased along with the deterioration of bone structure. However, CRBN knockout (KO) reduced blood glucose the levels and attenuated insulin resistance. What's more, CRBN ablation suppressed osteoclast differentiation and rescued diabetic bone loss in vivo, accompanied with decreased receptor activator of NF-kB ligand (RANKL), RANKL/osteoprotegerin (OPG), and tartrate-resistant acid phosphatase (TRAP) levels, as well as improved AMP-activated kinase (AMPK) α/acetyl-CoA carboxylase (ACC)αactivation. In vitro, suppressing CRBN expression could reduce RANKL-induced osteoclastogenesis, supported by the reduction of TRAP-positive cells. CRBN knockdown (KD) obviously reduced RANKL-induced activity of IκBα/nuclear factor-κB (NF-κB) pathway. In addition, osteoclast-specific genes expression levels stimulated by RANKL were also decreased by CRBN silence. More importantly, CRBN blockage increased phosphorylated AMPK-α and ACC-α expressions in RANKL-incubated cells. However, these processes could be abolished by suppressing AMPK-α with its inhibitor, Compound C. Collectively, our data suggested that CRBN is a potential treatment option against diabetes-induced osteolytic bone disease., (Copyright © 2018. Published by Elsevier Inc.)

Hemophilic arthropathy (HA) is one of the most common and typical manifestation in the course of recurrent bleeding episodes in patients with hemophilia. Clinical and subclinical joint bleeding episodes gradually lead to irreversible changes manifesting themselves as pain, progressing ankylosis, marked limitation of the range of motion, muscle atrophy and osteoporosis commonly concomitant with joint deformity resulting from chronic proliferative synovitis and both cartilage and bone degeneration leading to the final functional impairment of the joint. In spite of numerous studies, the pathophysiology of HA has not been fully elucidated, especially as regards immunopathological mechanisms which are associated with the subclinical and early stage of the disease and to be more precise, with chronic joint inflammation. It needs to be emphasized that the pathophysiological processes occurring in a joint with HA are most probably highly mediated by interactions within the cytokine network and other inflammatory mediators present in the tissues of affected joint. Among numerous compounds participating in the induction of an inflammatory process in the pathogenesis of HA, cytokines seem to play a leading role. The most important group controlling the disease seems to be well known inflammatory cytokines, including IL-1β, TNFα and IL-6. The second group with antagonistic effect is formed by anti-inflammatory cytokines such as IL-4 and IL-10. The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of HA with respect to cellular and intracellular signaling pathways is still under investigation. This review, summarizes and discusses the current knowledge about cytokine network in the pathogenesis of HA, indicating possible molecular and cellular mechanisms that may provide potential new therapeutic directions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

This retrospective study attempts to establish if a correlation exists between osteoporosis and hematopoiesis before and after adjuvant chemotherapy in the context of non-metastatic breast cancer. Osteoporosis is interpreted both as a direct marker of osteoblastic decline and as an indirect marker of increased bone marrow adiposity within the hematopoietic microenvironment. Patients from the "Centre du Sein" at CHUV (Centre Hospitalier Universitaire Vaudois) undergoing adjuvant chemotherapy were included in this study. Evolution of blood counts was studied in correlation with the osteoporosis status. Toxicity of chemotherapy was coded according to published probability of febrile neutropenia. One hundred forty-three women were included: mean age 52.1 ± 12.5 years, mean BMI (body mass index) 24.4 ± 4.1. BMD (bone mineral density) scored osteoporotic in 32% and osteopenic in 45%. Prior to chemotherapy, BMD was positively correlated with neutrophil (p < 0.001) and thrombocyte (p = 0.01) count; TBS (trabecular bone score) was not correlated with blood count. After the first cycle of chemotherapy, an increase of one point in TBS correlated with a decrease of 57% on the time to reach leucocyte nadir (p = 0.004). There was a positive correlation between BMD and risk of infection (p < 0.001). Our data demonstrates an association between osteoporosis and lower blood counts in a younger cohort than previously published, extending it for the first time to neutrophil counts in females. Our results suggest that the healthier the bone, the earlier the lowest leucocyte count value, prompting further research on this area.

Background: Positive anticyclic citrullinated peptide (anti-CCP+) is associated with bone loss in patients with rheumatoid arthritis (RA). However, whether overall positivity or specific levels of anti-CCP are associated with prevalent fracture or a 10-year probability of fracture remains unclear., Methods: This interim analysis of an RA registry was conducted at Chang Gung Memorial Hospital in Kaohsiung (CGMHK) for RA-related osteoporosis/fracture. Consecutive patients with RA who had visited the rheumatology clinic at CGMHK since September 1, 2014, and fulfilled the classification criteria of RA were enrolled. The demographics, disease duration, Disease activity in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR), lifestyle, evidence of previous fracture, risk factors of fracture in the Fracture Risk Assessment Tool (FRAX®), and FRAX® score of each participant were collected. Anti-CCP, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and bone mineral density (BMD) were measured at enrollment. The patients were grouped by positivity or quartiles of anti-CCP level (I-IV)., Results: Five hundred twenty-one patients with RA were enrolled through May 31, 2016. In total, 359 (68.9%) patients were anti-CCP+. Compared with anti-CCP- patients, anti-CCP+ patients had a significantly higher DAS28-ESR (p = 0.0001) and 10-year probability of major (15.0 [18.9] vs. 12.0 [15.3], p = 0.0461) or hip (5.0 [9.2] vs. 3.6 [8.2], p = 0.0118) fracture, but a significantly lower BMD of the FN (p = 0.0196). The rates of osteoporosis and previous fracture were comparable. There were 130, 127, 132, and 132 patients in groups I-IV, respectively. The DAS28-ESR was significantly different (p = 0.0001) among the groups and correlated to anti-CCP levels. The BMD and 10-year probability of major (p = 0.0067) and hip (p = 0.0013) fracture among the groups were also different., Conclusions: Anti-CCP+ RA patients had a higher 10-year probability of major or hip fracture, independent of anti-CCP levels, and a lower BMD of the FN than anti-CCP- patients.

Osteoimmunology is an interdisciplinary research field which combines the existing fields of osteology (bone biology) and immunology under one umbrella. The observation that contributed enormously to the emergence of osteoimmunology as an independent field of investigation was the enhanced bone loss in various inflammatory bone diseases such as rheumatoid arthritis, osteoporosis and periodontitis. T helper cells (Th1, Th2, Treg and Th17) along with various other immune cells (B cells, DC, macrophages etc.) are actively involved in bone homeostasis. The present review thus provides an overview of the nexus between these two prominent systems (Bone and Immune system) of an organism, which reside in a common niche (bone marrow) and thus cross-communicate to modulate their respective development. Investigations in the field of osteoimmunology thus promise the advent of new era in the field with novel therapeutics for bone loss in various inflammatory conditions. A molecular insight into the field of osteoimmunology can lead to novel approaches for the prevention and treatment of diverse inflammatory conditions such as osteoporosis, rheumatoid arthritis and osteoarthritis.

Osteoporosis is a recognised complication of axial spondyloarthritis (axSpA) and is thought to be due to functional impairment and the osteoclast-activating effects of proinflammatory cytokines. The development of autoantibodies to OPG (OPG-Ab) has been associated with severe osteoporosis and increased bone resorption in rheumatoid arthritis. In this study, we screened for the presence of OPG-Ab in axSpA and reviewed their clinical significance. We studied 134 patients, recruited from two centres in the United Kingdom. Their mean age was 47.5 years and 75% were male. Concentrations of OPG-Ab were related to bone mineral density (BMD) and fracture history using linear and logistic regression models adjusting for age, gender, disease duration and activity, body mass index and bisphosphonate use. We detected OPG-Ab in 11/134 patients (8.2%). Femoral neck and total hip BMD were significantly reduced in OPG-Ab positive patients (0.827 vs. 0.967 g/cm 2 , p = 0.008 and 0.868 vs. 1.028 g/cm 2 , p = 0.002, respectively). Regression analysis showed that the presence of OPG-Ab was independently associated with total hip osteopenia (OR adj 24.2; 95% CI 2.57, 228) and history of fractures (OR adj 10.5; 95% CI 2.07, 53.3). OPG-Ab concentration was associated with total hip BMD in g/cm 2 (ß = -1.15; 95% CI -0.25, -0.04). There were no associations between OPG-Ab concentration and bone turnover markers, but free sRANKL concentrations were lower in OPG-Ab-positive patients (median 0.04 vs. 0.11 pmol/L, p = 0.050). We conclude that OPG-Ab are associated with hip BMD and fractures in axSpA suggesting that they may contribute to the pathogenesis of bone loss in some patients with this condition.

The netrin family of proteins are involved in axon guidance during central nervous system development. In vertebrates, two membrane bound forms and five secreted forms of netrin have been reported. In addition to their critical role in neural morphogenesis, a growing number of reports suggest that netrin family proteins also play a role in inflammatory conditions, angiogenesis, and tumorigenesis. In these processes, Unc5 and DCC family proteins serve as receptors of netrin proteins. Recently, it was reported that some netrin family proteins may be involved in the pathogenesis of skeletal diseases including osteoporosis and arthritis. For example, administration of secreted netrin family proteins such as netrin 1 and netrin 4 has prophylactic potential in pathogenic bone degradation in mice. However, netrin 1 blocking antibody also protects mice from inflammatory bone destruction. Therefore, netrin family proteins are involved in the regulation of bone homeostasis, but their bona fide roles in the skeletal system remain controversial. In this review, we discuss the osteo-innate-immune functions of the netrin family of proteins, and summarize their therapeutic potential., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose of Review: Mounting evidence supporting the critical contribution of macrophages, in particular osteal macrophages, to bone regeneration is reviewed. We specifically examine the potential role of macrophages in the basic multicellular units coordinating lifelong bone regeneration via remodelling and bone regeneration in response to injury. We review and discuss the distinctions between macrophage and osteoclast contributions to bone homeostasis, particularly the dichotomous role of the colony-stimulating factor 1-colony-stimulating factor 1 receptor axis., Recent Findings: The impact of inflammation associated with aging and other hallmarks of aging, including senescence, on macrophage function is addressed in the context of osteoporosis and delayed fracture repair. Resident macrophages versus recruited macrophage contributions to fracture healing are also discussed. We identify some of the remaining knowledge gaps that will need to be closed in order to maximise benefits from therapeutically modulating or mimicking the function of macrophages to improve bone health and regeneration over a lifetime.

Purpose of the Review: In this review, we present the role of regulatory T (Treg) cells in bone remodelling and bone-related disease such as osteoporosis or inflammatory bone loss. We also discuss the cellular and molecular mechanism how Treg cells regulate osteoclastogenesis., Recent Findings: Treg cells could regulate osteoclastogenesis by secreting TGF-β and IL-10 as well as IL-4 cytokines. Moreover, Treg cells can additionally regulate osteoclast differentiation, in a cell-to-cell contact via the cytotoxic T lymphocyte antigen (CTLA-4). The latter induces the apoptosis of osteoclasts dependent on CD80/86 in vitro and in vivo. Treg cells mediate immunosuppressive function that controls undesired immune reactions, such as autoimmunity. Recently, Treg cells have been shown to influence non-immunological processes, such as bone homeostasis. Accumulated evidences have demonstrated that Treg cells can suppress osteoclast differentiation in vitro and in vivo.

Background: A higher risk of developing osteopenia/ osteoporosis has been seen in HIV-infected patients. We compared HIV-infected patients, all treated with combination antiretroviral therapy (cART), with a low bone mineral density (BMD) (T-score < -1) to those with a normal BMD (T-score > -1), examining the relation with T-cell activation and bone turnover markers (c-terminal telopeptide (CTX) and procollagen type 1 amino-terminal propeptide (P1NP))., Methods: In this single visit pilot study, bone turnover markers, T-cell activation (CD38 + HLA - DR +) and senescence (CD57+) of T cells were measured in patients who had previously undergone dual energy X-ray absorptiometry scanning., Results: All study participants (n = 16) were male, on cART, with a median age of 61 years (IQR 56-66). Nine patients had osteopenia/osteoporosis. When comparing the patients with osteopenia/osteoporosis with those with a normal BMD, no differences in activation and senescence were found. A relation was seen between higher bone formation (P1NP) and patients who were on cART for longer. The median length of cART use was 5.5 years (IQR 4.5-7.8), with all patients on nucleoside reverse transcriptase inhibitors, 88% on tenofovir, 63% on non-nucleoside reverse transcriptase inhibitors (NNRTIs) and 38% on protease inhibitors. Osteopenia/osteoporosis was seen in 100% of the patients on protease inhibitors versus 30% of those on NNRTIs., Conclusion: This study did not find an association between activated T cells and BMD, thus did not explain the higher prevalence of osteopenia/osteoporosis in HIV-infected patients. Interestingly, this small pilot showed that cART might influence BMD, with a possible negative effect for protease inhibitors and a possible protective effect for NNRTIs. These results warrant further investigation.

In 1973, Singleton and Merten described a new syndrome in 2 female probands with aortic and cardiac valve calcifications, early loss of secondary dentition, and widened medullary cavities of the phalanges. In 1984, Aicardi and Goutières defined a phenotype resembling congenital viral infection with basal ganglia calcification and increased protein content in the cerebrospinal fluid. Between 2006 and 2012, mutations in 6 different genes were described to be associated with Aicardi-Goutières syndrome, specifically-TREX1, RNASEH2A, RNASEH2B, RNASEH2C, ADAR, and SAMHD1. More recently, mutations in IFIH1 were reported in a variety of neuroimmunological phenotypes, including Aicardi-Goutières syndrome, while a specific Arg822Gln mutation in IFIH1 was described in 3 discrete families with Singleton-Merten syndrome (SMS). IFIH1 encodes for melanoma differentiation-associated gene 5 (MDA5), and all mutations identified to date have been associated with an enhanced interferon response in affected individuals. In this study, we present a male child demonstrating recurrent febrile episodes, spasticity, and basal ganglia calcification suggestive of Aicardi-Goutières syndrome, who carries the same Arg822Gln mutation in IFIH1 previously associated with SMS. We conclude that both diseases are part of the interferonopathy grouping and that the Arg822Gln mutation in IFIH1 can cause a spectrum of disease, including neurological involvement.

Objective: The aim of this study was to gain a better understanding of the molecular mechanisms and identify more critical genes associated with the pathogenesis of postmenopausal osteoporosis (PMOP)., Materials and Methods: Microarray data of GSE13850 were download from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified either in B cells from postmenopausal female nonsmokers with high bone mineral density (BMD) compared with those with low BMD (defined as DEG1 group) or in B cells from postmenopausal female smokers with high BMD compared with postmenopausal female nonsmokers with high BMD (defined as DEG2 group). Gene ontology and immune-related functional enrichment analysis of DEGs were performed. Additionally, the protein-protein interaction network of all DEGs was constructed and subnetworks of the hub genes were extracted., Results: A total of 51 DEGs were identified in the DEG1 group, including 30 up- and 21 downregulated genes. Besides, 86 DEGs were identified in the DEG2 group, of which 46 were upregulated and 40 were downregulated. Immune enrichment analysis showed DEGs were mainly enriched in functions of CD molecules and chemokines and receptor, and the upregulated gene interleukin 4 receptor (IL-4R) was significantly enriched. Moreover, guanine nucleotide-binding protein G (GNAI2), filamin A alpha (FLNA), and transforming growth factor-β1 (TGFB1) were hub proteins in the protein-protein interaction network., Conclusion: IL-4R, GNAI2, FLNA, and TGFB1 may be potential target genes associated with the pathogenesis of PMOP. In particular, FLNA, and TGFB1 may be affected by smoking, a risk factor of PMOP., (Copyright © 2017. Published by Elsevier B.V.)

Objective: Our study aimed to explore the anti-osteoporotic effect of rutin (quercetin-3-O-rutinose) on ovariectomized female rats., Materials and Methods: An ovariectomized (OVX) rat model of osteoporosis was employed to evaluate the anti-osteoporotic potency of rutin. One week after surgery, the rats were administered intragastrically with rutin or saline once daily respectively for 3 months. Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry (DEXA). The bone microstructure was analyzed by hematoxylin and eosin (HE) staining of the left tibia histomorphology. Estradiol, IL-6, and TNF-α were measured by ELISA kits., Results: The results showed that rutin significantly improved the bone mineral density (BMD) and increased the level of inflammatory factor of IL-6, TNF-α, and INF-γ in OVX rats. Rutin turned bone trabecula to be thickened and dense, and kept regular array. Moreover, rutin significantly improved the average thickness of trabecular bone and the average bone volume fraction., Conclusions: Rutin possessed with significant anti-osteoporotic activity, which can be considered as an idealistic anti-osteoporotic candidate for human osteoporosis diseases.

Alendronate regulates the activity of osteoclasts and healing of osteoporosis. This study investigated the effect of alendronate on bone healing and changes in the levels of cytokines. Bilateral ovaries of 10 adult female rabbits were removed surgically in aseptic condition to establish the animal model of osteoporosis. Five rabbits in group A were treated with alendronate (1.15 mg·kg -1 ·week -1 ) once a week by a stomach tube, whereas the remaining 5 in group B were treated with physiological saline. The success of the animal model establishment and the efficacy of alendronate treatment were evaluated by the sports ability score and the Basso, Beattie, and Bresnahan (BBB) score; the healing degree of osteoporosis was determined by X-ray analysis and measurement of biomechanical properties; the changes in the levels of related cytokines were measured by enzyme-linked immunosorbent assay (ELISA) and immunohistochemical staining. Treatment improved dyskinesia of the animals in group A than that in group B, with significant improvement occurring in the 4th week of treatment. The BBB score of the group A animals revealed movements similar to normal, but that of the group B animals exhibited significant motor disturbance (P < 0.01). X-ray examination showed that with time, the X-ray ratings increased. Measurement of the biomechanical properties further showed that alendronate had a positive effect on osteoporosis healing. The results of ELISA and immunohistochemistry showed that the levels of ALP, BMP-2, bFGF, and IGF-1 were upregulated in group A. In conclusion, alendronate accelerated osteoporosis healing probably via certain cytokine-related mechanism.

Osteoporosis (OP) and osteoarthritis (OA) are the most common joint diseases, with a high incidence in the elderly population. OP is characterized by trabecular bone remodeling and reabsorption, whereas articular cartilage and subchondral bone remodeling are major features of OA. Although classically considered as independent or even conflicting processes, clinical coexistence of OP and OA was recently described. Transglutaminase 2 (TG2) expression is considered a biomarker of OA, but its role in osteoporotic bone remodeling is still uncertain. We investigated TG2 and bone biological markers (Osteocalcin, Osteopontin, and Sclerostin) in osteoporotic and osteoarthritic osteocartilagineous tissue (n = 54) and human chondrocyte cultures in vitro by immunohistochemistry, immunofluorescence and RT-PCR. Histomorphometric evaluation of bone trabecular remodeling was also performed. In cartilage, TG2 expression was faint in control and OP and significantly less than in OA and OP + OA chondrocytes; the opposite was found for Osteocalcin, whereas Osteopontin and Sclerostin expression was similar. In the subchondral trabecular bone, osteocytes/osteoblasts TG2 expression was slight and similar comparing control, OP, OA, and OP + OA group, whereas Osteocalcin and Osteopontin expression was lower in OP compared to control, OA and OP + OA. Increased TG2 and reduced Osteocalcin expression were maintained in human osteoarthritic chondrocytes in vitro. Histomorphometric analysis confirmed reduced trabecular bone mass in OP and OP + OA compared with OA patients. TG2 represented a suitable biomarker of osteoarthritic chondrocyte activation, whereas osteocalcin and osteopontin characterized osteoporotic osteocyte/osteoblast changes; differences were lost in OP + OA patients, suggesting careful consideration when coexistence of the two diseases occurs.

Background: Obesity was traditionally considered as a positive regulator on the strength of bone. With the in-depth study, obesity is considered as a major risk factor for osteoporosis. Some proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are the factors that fat uses to negatively regulate bone metabolism., Objective: This review was aimed to summarize and critically discuss the convincing evidence for the therapeutic effectiveness of pro-inflammatory cytokines for the treatment of obesity-related bone disorders., Results: Obese people and animals show a higher level of serum TNF-α and IL-6, which are produced by macrophages derived from adipose tissue. These pro-inflammatory cytokines regulate the proliferation and apoptosis of adipocyte, promote lipolysis, inhibit lipid synthesis and decrease blood lipids through autocrine and paracrine way. On the other hand, TNF-α and IL-6 regulate bone metabolism through the endocrine way. Several reports suggest that TNF-α is a negative regulator of osteoblast at some stages of differentiation and positively regulates osteoclast proliferation and differentiation. In contrast, IL-6 influences osteoblasts and osteoclasts through complex mechanisms, which reflect dual effects. In addition, TNF-α and IL-6 may regulate bone metabolism indirectly by regulating adiponectin and leptin released from adipocytes., Conclusion: In this review, we first summarize the role of TNF-α and IL-6 in lipid and bone metabolisms. We further discuss how TNF-α and IL-6 regulate the communication between fat and bone, and their pathological roles in obesity-related bone disorders. Lastly, we discuss the possibility of using pro-inflammatory signaling pathway as a therapeutic target to develop drug for obesity-related bone disorders., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

New evidence of the interactions between the immune system and bone has accumulated in bone diseases, including osteoporosis, periodontitis and rheumatoid arthritis. A marked imbalance between bone resorption and formation is central to the onset of pathological bone loss. Osteoimmunology has revealed that the immune system, including T cells, B cells and inflammatory cytokines, is a key regulator of both osteoclasts and osteoblasts. Th1 cells, which differentiate from CD4+T cells, are thought to play a major function during bone loss. Moreover, the correlated expression of Th1 cytokines (interleukin-12 (IL-12), interferon-γ (IFN-γ)) and bone-resorbing cytokines (tumor necrosis factor-α (TNF-α), IL-1) also plays a key role during inflammatory induced bone resorption. Furthermore, a relatively new member of the CD4+T cell family Th17 displays the ability to promote osteoclast activity. The effect of IFN-γ and IL-17 released by Th 17 cells on pre-osteoclast proliferation, differentiation and apoptosis provides the preliminary basis for the immune mechanism of pathological bone loss. The role of B cells in osteoimmunological interactions has long been suspected based on findings of B cells as active regulators of the RANK/RANKL/OPG axis. Pathological bone loss, including osteoporosis and human immunodeficiency virus-associated bone loss, are related to the altered RANKL/OPG through modified production by B cells, supporting this assumption. All of the above evidence may provide new theoretical explanations for the relationship between bone metabolism and the immune system as well as offer perspectives for the prevention and treatment of pathological bone loss., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The higher risk of osteoporosis and fracture associated with HIV infection and certain antiretrovirals has been well established and the need for risk stratification among older adults increasingly recognized. This review focuses upon emerging data on bone complications with HIV/HCV coinfection, in children and adolescents, and with pre-exposure prophylaxis (PrEP), as well as new management strategies to minimize the negative effects of ART on bone.

Rapid progress has been made in exploring the connections between the skeletal system and the immune system over the past decade. Bone tissue forms developmental niches for hematopoietic stem cells, and activated immune cells are involved in bone metabolism regulation and are potent mediators of osteoporosis and bone erosion under pathological conditions. The interdisciplinary field of osteoimmunology has emerged to pool the knowledge of the interdependence of these two systems, including the shared ligands and receptors, their crosstalk and interaction, and common intracellular signaling pathways with bidirectional influence. The receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) triad is the key vinculum, with multifaceted potency, being not only essential for osteoclastogenesis but also critical for lymph node organogenesis and lymphopoiesis as well as for immune regulation. In this review, we summarize the progress in this area, focusing on those aspects of interest concerning rheumatic diseases.

Background: Autoantibodies such as anti-citrullinated protein antibodies (ACPA) are major risk factors for articular bone destruction from the earliest phases of rheumatoid arthritis (RA). The aim of the current study was to determine whether RA-associated autoantibodies also impact on systemic bone loss in patients with early disease., Methods: Systemic bone mineral density (BMD) was measured in the lumbar spine and the hip in 155 consecutive treatment-naïve patients with early RA (median symptom duration 13 weeks). Demographic and disease-specific parameters, including clinical disease activity, ultrasonographic (US) examination of the hands and wrists, radiographic scoring of joint damage, ACPA and rheumatoid factor (RF) levels were recorded from all patients. Reduced BMD was defined as Z score ≤ -1 SD and analysed in relation to disease-related characteristics and autoantibody subgroups., Results: Reduced BMD was found in 25.5 % of the patients in the spine and 19.4 % in the hip. Symptom duration, clinical and US disease activity, functional disability and radiographic damage did not significantly impact on spine and hip BMD loss in regression analyses adjusted for possible confounders (age, gender, menopausal status, current smoking, body mass index). In contrast, ACPA positivity (at any level) negatively affected the spine Z-score (adjusted OR (95 % CI) 2.76 (1.19 to 6.42)); the hip Z score was affected by high titres only (adjusted OR (95 % CI) 2.96 (1.15 to 7.66)). The association of ACPA with reduced BMD in the spine was confirmed even at low levels of RF (adjusted OR (95 % CI) 2.65 (1.01 to 7.24)), but was further increased by concomitant high RF (adjusted OR (95 % CI) 3.38 (1.11 to 10.34)). In contrast, Z scores in the hip were significantly reduced only in association with high ACPA and RF (adjusted OR (95 % CI) 4.96 (1.48 to 16.64))., Conclusions: Systemic BMD in patients with early RA is reduced in relation with ACPA positivity and high RF levels. This finding supports the notion that RA-associated autoimmunity may have a direct causative role in bone remodeling.

Objective: ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA., Methods: We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction., Results: Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease., Conclusion: As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity., Trial Registration: ClinicalTrials.gov, NCT01111240., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Osteoporosis develops when the rate of osteoclastic bone breakdown (resorption) exceeds that of osteoblastic bone formation, which leads to loss of BMD and deterioration of bone structure and strength. Osteoporosis increases the risk of fragility fractures, a cause of substantial morbidity and mortality, especially in elderly patients. This imbalance between bone formation and bone resorption is brought about by natural ageing processes, but is frequently exacerbated by a number of pathological conditions. Of importance to the aetiology of osteoporosis are findings over the past two decades attesting to a deep integration of the skeletal system with the immune system (the immuno-skeletal interface (ISI)). Although protective of the skeleton under physiological conditions, the ISI might contribute to bone destruction in a growing number of pathophysiological states. Although numerous research groups have investigated how the immune system affects basal and pathological osteoclastic bone resorption, recent findings suggest that the reach of the adaptive immune response extends to the regulation of osteoblastic bone formation. This Review examines the evolution of the field of osteoimmunology and how advances in our understanding of the ISI might lead to novel approaches to prevent and treat bone loss, and avert fractures.

Osteoporosis is an age-related progressive bone disease. Recent advances in epigenetics, cell biology, osteoimmunology, and genetic epidemiology have unraveled new mechanisms and players underlying the pathology of osteoporosis, supporting a model of age-related dysregulation and crosstalk in the bone microenvironment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically heterogenic group of Mendelian diseases with a constitutive activation of this pathway that might present as atypical, severe, early onset rheumatic diseases. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common. Recent studies have implicated abnormal responses to nucleic acid stimuli or defective regulation of downstream effector molecules in disease pathogenesis. As observed for IL1-β and autoinflammatory diseases, knowledge of the defects responsible for type I interferonopathies will likely promote the development of targeted therapy.

Microscopic fractures (so-called microcracks) or traumatic macrofractures require bone, as the basic scaffold of the human body, to have a high regenerative capability. In order to be able to provide this regenerative capability, bone is in a constant process of remodeling. This finely tuned homeostasis of bone formation and degradation can become disrupted, which leads to osteoporosis or other bone disorders. It has been shown that the immune system is substantially involved in the regulation of bone homeostasis and that chronic inflammation in particular can disturb this balance; therefore, this article reviews the osteoimmunological aspects contributing to osteoporosis and other diseases associated with bone degradation.

In recent years the great progress in knowledge on bone cell biology has allowed identification of molecular structures that can be targeted with pinpoint precision (druggable targets). Osteoclasts are regulated via the RANK-RANK-ligand (RANKL) signaling pathway and osteoblasts via the Wnt signaling pathway, both of which can be influenced for therapeutic measures. As a result the number of (functional) osteoclasts can be decreased or the genesis of osteoblasts can be increased and bone resorption is inhibited or bone formation is enhanced, respectively. Osteoclasts degrade collagen through cathepsin K and inactivation of this enzyme stabilizes the bone matrix; however, as osteoclasts are still able to maintain a stimulatory cross-talk with osteoblasts, formation of new bone will not be reduced. Parathyroid hormone-related protein plays a role in endochondral ossification and a synthetic analogue of this protein may have potent bone anabolic activity; however, the use of such new and highly efficient therapeutic principles comes with new questions and uncertainties on the sequence of therapies, duration of therapy, long-term side effects, undesired activation of metabolic pathways and effectiveness in comparison to other strategies of fracture prevention.

A balance between bone formation and bone resorption is critical for the maintenance of bone mass. In many pathological conditions, including chronic inflammation, uncontrolled activation of osteoclast differentiation often causes excessive bone resorption that results in osteoporosis. In this study, we identified the osteopenia phenotype of mice lacking Usp18 (also called Ubp43), which is a deISGylating enzyme and is known as a negative regulator of type I IFN signaling. The expression of Usp18 was induced in preosteoclasts upon receptor activator of NF-κB ligand (RANKL) treatment. In an in vitro osteoclast-differentiation assay, bone marrow macrophages from Usp18-deficient mice exhibited an enhanced differentiation to multinucleated cells, elevated activation of NFATc1, and an increased expression of osteoclast marker genes upon RANKL treatment. Furthermore, in vitro quantification of bone resorption revealed a great increase in osteoclastic activities in Usp18-deficient cells. Interestingly, proinflammatory cytokine genes, such as IP-10 (CXCL10), were highly expressed in Usp18-deficient bone marrow macrophages upon RANKL treatment compared with wild-type cells. In addition, serum cytokine levels, especially IP-10, were significantly high in Usp18-knockout mice. In sum, we suggest that, although type I IFN is known to restrict osteoclast differentiation, the exaggerated activation of the type I IFN response in Usp18-knockout mice causes an osteopenia phenotype in mice., (Copyright © 2016 by The American Association of Immunologists, Inc.)