Stimulate Bone Resorption Research Articles

Differential protein expression of osteoclastogenic factors in odontogenic cysts and tumors.

The osteolytic activity of odontogenic cysts and tumors is directly associated with their growth and aggressiveness. The influence of proteins expressed by epithelial and mesenchymal cells on this biological event differs between indolent cystic lesions, aggressive cystic lesions, and odontogenic tumors. The objective of this study was to compare the immunohistochemical expression of factors that stimulate (receptor activator of nuclear factor kappa-Β ligand - RANKL, cathepsin K - CatK and matrix metallopeptidase 8 - MMP-8) and inhibit (osteoprotegerin - OPG) osteoclastogenesis between dentigerous cyst (DC), glandular odontogenic cyst (GOC), odontogenic keratocyst (OKC), and ameloblastoma (AB). Paraffin-embedded sections of nine DCs, nine GOCs, 20 OKCs, 21 ABs, and four dental follicles (DFs) were subjected to immunohistochemistry. Immunoreactivity was analyzed semiquantitatively and quantitatively in epithelium and connective tissue, respectively. The proteins were immunoexpressed in epithelial and mesenchymal cells of all lesions studied. The expression of RANKL and CatK was higher in OKC, AB, and GOC (p<0.005). Higher expression of OPG was found in DF and DC compared to the other markers (p<0.005). MMP-8 expression was high in GOC and OKC. This study demonstrated the differential expression of factors that inhibit and stimulate bone resorption during the development of DC, GOC, OKC, and AB. Higher expression of RANKL and CatK was observed in more aggressive lesions. OPG appears to be one of the molecules responsible for the slower growth of DC.

Stimulation of osteoclast formation and bone resorption by glucocorticoids: Synergistic interactions with the calcium regulating hormones parathyroid hormone and 1,25(OH)2-vitamin D3.

Osteoporosis is a significant health problem, with skeletal fractures increasing morbidity and mortality. Excess glucocorticoids (GC) represents the leading cause of secondary osteoporosis. The first phase of glucocorticoid-induced osteoporosis is increased bone resorption. In this Chapter, in vitro studies of the direct glucocorticoid receptor (GR) mediated cellular effects of GC on osteoclasts to affect bone resorption and indirect effects on osteoblast lineage cells to increase the RANKL/OPG ratio and stimulate osteoclastogenesis and bone resorption are reviewed in detail, together with detailed descriptions of in vivo effects of GC in different portions of the skeleton in research animals and humans. Brief sections are devoted to contrasting functions of GC in osteonecrosis, vitamin D formation, in vitro and in vivo bone resorptive actions dependent on vitamin D receptor and vitamin D toxicity, as well as the molecular basis of GR action. Included are also more detailed assessments of the interactions of GC with the major calcium regulating hormones, 1,25(OH)2-vitamin D3 and parathyroid hormone, describing the in vitro increases in RANKL/OPG ratios, osteoclastogenesis and synergistic bone resorption that occurs when GC is combined with either 1,25(OH)2-vitamin D3 or parathyroid hormone. Additionally, a molecular basic for the synergistic interaction of GC with 1,25(OH)2-vitamin D3 is provided along with a suggested molecular basic for the interaction between GC and parathyroid hormone.

Association of Genetic Polymorphism of Tumor Necrosis Factor-α in the Development of Coronary Heart Disease in Elderly Patients

The research project outlines a new look at the concept of "inflammaging" and the role of the subclinical inflammatory process in various age-associated pathology, in particular coronary heart disease. Particular attention is paid to the tumor necrosis factor-α -cytokine, which plays an important role in the pathogenesis of chronic inflammatory processes and in the aging process. The increased content of tumor necrosis factor-α leads to the emergence and accumulation of various diseases, disability and mortality of elderly and senile people.&#x0D; Tumor necrosis factor-α influences various risk factors for cardiovascular pathology. This substance aggravates various breakdowns in metabolism, primarily causing insulin resistance. Tumor necrosis factor-α is a key cytokine that stimulates bone resorption (osteoporosis) and sarcopenia. Currently available data prove the important role of tumor necrosis factor-α in various age-associated pathologies.

Metabolic acidosis regulates RGS16 and G protein signaling in osteoblasts.

Chronic metabolic acidosis stimulates cell-mediated net Ca2+ efflux from bone mediated by increased osteoblastic cyclooxygenase 2, leading to prostaglandin E2-induced stimulation of receptor activator of NF-κB ligand-induced osteoclastic bone resorption. Ovarian cancer G protein-coupled receptor-1 (OGR1), an osteoblastic H+-sensing G protein-coupled receptor, is activated by acidosis and leads to increased bone resorption. As regulator of G protein signaling (RGS) proteins limit GPCR signaling, we tested whether RGS proteins themselves are regulated by metabolic acidosis. Primary osteoblasts were isolated from neonatal mouse calvariae and incubated in physiological neutral or acidic (MET) medium. Cells were collected, and RNA was extracted for real-time PCR analysis with mRNA levels normalized to ribosomal protein L13a. RGS1, RGS2, RGS3, RGS4, RGS10, RGS11, and RGS18 mRNA did not differ between MET and neutral medium; however, by 30 min, MET decreased RGS16, which persisted for 60 min and 3 h. Incubation of osteoblasts with the OGR1 inhibitor CuCl2 inhibited the MET-induced increase in RGS16 mRNA. Gallein, a specific inhibitor of Gβγ signaling, was used to determine if downstream signaling by the βγ-subunit was critical for the response to acidosis. Gallein decreased net Ca2+ efflux from calvariae and cyclooxygenase 2 and receptor activator of NF-κB ligand gene expression from isolated osteoblasts. These results indicate that regulation of RGS16 plays an important role in modulating the response of the osteoblastic GPCR OGR1 to metabolic acidosis and subsequent stimulation of osteoclastic bone resorption.NEW & NOTEWORTHY The results presented in this study indicate that regulation of regulator of G protein signaling 16 and G protein signaling in the osteoblast plays an important role in modulating the response of osteoblastic ovarian cancer G protein-coupled receptor 1 (OGR1) to metabolic acidosis and the subsequent stimulation of osteoclastic bone resorption. Further characterization of the regulation of OGR1 in metabolic acidosis-induced bone resorption will help in understanding bone loss in acidotic patients with chronic kidney disease.

Association between exposure to fine particulate matter and osteoporosis: a population-based cohort study

SummaryLong-term environmental air pollution exposure was associated with osteoporosis’ risk in a cohort of women at high risk of fracture. Cortical sites seemed to be more susceptible to the exposure’s effect.IntroductionEnvironmental air pollution has been associated with disruption of bone health at a molecular level. Particulate matter (PM) exposure can simultaneously stimulate bone resorption and halt bone formation. The primary aim of the present study is to describe the association between long-term exposure to PM and osteoporosis in a large cohort of women at high risk of fracture.MethodsClinical, demographic, and densitometric data were extracted from the DeFRAcalc79 dataset, which gathers data on women at risk for osteoporosis. Data on the monitoring of PM10 and PM2.5 concentrations were retrieved from the Italian institute of environment protection and research (Istituto Superiore per la Protezione e la Ricerca Ambientale, ISPRA). Generalized linear models with robust estimators were employed to determine the relationship between BMD and PM long-term exposure.ResultsA total 59,950 women from 110 Italian provinces were included in the study. PM 2.5 exposure was negatively associated with T-score levels at the femoral neck (β −0.005, 95 CI −0.007 to −0.003) and lumbar spine (β −0.003, 95% CI −0.006 to −0.001). Chronic exposure to PM2.5 above 25 μg/m3 was associated with a 16% higher risk of having osteoporotic T-score at any site (aOR 1.161, 95% CI 1.105 to 1.220), and exposure to PM10 above 30 μg/m3 was associated with a 15% higher risk of having osteoporotic T-score at any site (aOR 1.148, 95% CI 1.098 to 1.200).ConclusionLong-term exposure to air pollution was associated with higher risk of osteoporosis. Femoral neck site seemed to be more susceptible to the detrimental effect of PM exposure than lumbar spine site.Key messageExposure to air pollution is associated with osteoporosis, mainly at femoral site.

Osteoporosis is accompanied by reduced CD274 expression in human bone marrow-derived mesenchymal stem cells.

Underlying pathomechanisms of osteoporosis are still not fully elucidated. Cell-based therapy approaches pose new possibilities to treat osteoporosis and its complications. The aim of this study was to quantify differences in human bone marrow-derived mesenchymal stem cells (hBMSCs) between healthy donors and those suffering from clinically manifest osteoporosis. Cell samples of seven donors for each group were selected retrospectively from the hBMSC cell bank of the Trauma Department of Hannover Medical School. Cells were evaluated for their adipogenic, osteogenic and chondrogenic differentiation potential, for their proliferation potential and expression of surface antigens. Furthermore, a RT2 Osteoporosis Profiler PCR array, as well as quantitative real-time PCR were carried out to evaluate changes in gene expression. Cultivated hBMSCs from osteoporotic donors showed significantly lower cell surface expression of CD274 (4.98 % ± 2.38 %) than those from the control group (26.03 % ± 13.39 %; p = 0.007), as assessed by flow cytometry. In osteoporotic patients, genes involved in inhibition of the anabolic WNT signalling pathway and those associated with stimulation of bone resorption were significantly upregulated. Apart from these changes, no significant differences were found for the other cell surface antigens, adipogenic, osteogenic and chondrogenic differentiation ability as well as proliferation potential. These findings supported the theory of an influence of CD274 on the regulation of bone metabolism. CD274 might be a promising target for further investigations of the pathogenesis of osteoporosis and of cell-based therapies involving MSCs.

Effect of Age on Bone Structure Parameters in Laying Hens.

Simple SummaryLaying hens supply calcium to their eggshells via a process of dynamic bone formation and resorption called remodeling. As hens age, their bone becomes weak and brittle due to an imbalance in remodeling, resulting in bone disorders. Osteoporosis, characterized by bone mass loss and increased risk of fractures, is a serious problem in the egg industry, affecting both productivity and animal welfare. Nonetheless, the mechanisms of age-related osteoporosis remain unknown. We evaluated differences in bone structure between age groups, using microscopy and 3D imaging. Bone quality was reduced by an increase in porosity, with loss of volume, contributing to age-related osteoporosis.Changes in medullary and cortical bone structure with age remain unclear. Twenty Hy-Line W36 hens, 25 or 52 weeks of age, were euthanized, and both tibiae were collected when an egg was present in the magnum. Serial cross sections of the tibiae were stained with Alcian blue. The bones were scanned using micro-computed tomography. Trabecular width (Tb.Wi) was significantly higher (p < 0.05) in 25-week-old hens, whereas medullary bone tissue volume (TV) was significantly higher (p < 0.01) in 52-week-old hens. 25-week-old hens had significantly higher (p < 0.01) bone volume fraction (BVF = calcified tissue / TV). Moreover, the cortical bone parameters were significantly higher (TV and bone mineral content (BMC) at p < 0.05, and bone volume (BV) and BVF at p < 0.01) in younger hens. Open porosity and total porosity, which indicate less density, were significantly higher (p < 0.01) in older hens. Older hens showed significantly higher (p < 0.01) tibial diaphysis TV than younger hens. Younger hens had significantly higher (p < 0.01) BV, BVF and bone mineral density (BMD) of the tibial diaphysis. These findings reveal that reductions in medullary bone quality might be associated with age-related low estrogen levels and stimulation of osteoclastic bone resorption by parathyroid hormone. Cortical bone quality decreased with enlargement of the Haversian canals and loss of volume, with a longer egg-laying period leading to osteoporosis.

Osteoporosis prevention in an extraordinary hibernating bear.

Disuse osteoporosis results from physical inactivity. Reduced mechanical loading of bone stimulates bone resorption leading to bone loss, decreased mechanical properties, and increased fracture risk. Compensatory mechanisms evolved in hibernators to preserve skeletal muscle and bone during the prolonged physical inactivity that occurs during annual hibernation. This paper reports the preservation of bone properties in an exceptionally old black bear that was physically inactive for about 6months annually for 31years. The biological mechanisms that preserve bone during prolonged disuse during hibernation are also reviewed.

Sclareol inhibits RANKL-induced osteoclastogenesis and promotes osteoblastogenesis through promoting CCN1 expression via repressing the MAPK pathway.

Osteoclasts are crucial cellular components of bone and are the cause of various bone problems like osteoporosis. Various biological activities such as anti-tumorous, anti-inflammatory, antibacterial, and immunomodulatory function are influenced by Sclareol, as a natural diterpene compound. However, studies on the effect and mechanism of Sclareol on osteoporosis are rare. In the current research, the influence of Sclareol on osteoclastogenesis and osteoblastogenesis was targeted to be discovered in ovariectomy (OVX)-induced animal models and in vitro. The expression levels of osteoclast-related genes such as c-Fos, NFATc1, and CTSK were detected by RT-qPCR and western blotting to understand the inhibition of Sclareol on the creation of osteoclast. The influence of Sclareol on osteoblastogenesis and the expression of osteoblastogenic markers were also examined. Sclareol inhibited the osteoclastogenesis caused by receptor activator of nuclear factor-κB ligand (RANKL) which promoted osteoblastogenesis through upregulating the expression of cysteine-rich protein 61 (CYR61/CCN1), which is a matricellular protein of the CCN family. The p-ERK and p-P38 protein expression levels were considerably downregulated by Sclareol. Furthermore, CCN1 overexpression partially mimicked the inhibitory effect of Sclareol, while the opposite results were obtained after CCN1 silencing. Additionally, Sclareol protected against loss of bones in an osteoporosis mouse model generated by OVX. The acquired results indicated that Sclareol represses RANKL-induced osteoclastogenesis and promotes osteoblastogenesis via promoting the expression of CCN1 by constraining the mitogen-activated protein kinase (MAPK) pathway. Our findings proposed that for the avoidance and treatment of osteoclast-linked disorders, Sclareol is a potentially effective drug. A proposed model for mediated regulation of osteoclastogenesis and osteoblastogenesis by Sclareol. The basic model of the process by which Sclareol prevents osteoclastogenesis and promotes osteoblastogenesis. Sclareol may increase the expression of CCN1 through inhibiting the MAPK pathway, thereby inhibiting osteoclast differentiation and attenuating bone resorption. Sclareol represses the expression of c-Fos, which stimulates the formation of osteoclast. In contrast, Sclareol promotes osteoblast differentiation by upregulating Runx2 expression, thereby improving the formation of bones. Consequently, Sclareol protects against loss of bones by regulating the stability of bone makeover via inhibition of bone formation and stimulation of bone resorption. Graphical Headlights 1. Sclareol represses RANKL-induced osteoclastogenesis. 2. Sclareol promotes osteoblast differentiation. 3. Sclareol inhibits the MAPK pathway through induction of CCN1. 4. Sclareol protects against bone loss by regulating the balance of bone remodeling via inhibition of bone formation and stimulation of bone resorption.

Association of Ki-67 Level on Bone Destruction in Chronic Suppurative Otitis Media Patients with Cholesteatoma

Background: Chronic suppurative otitis media (CSOM) with cholesteatoma is one of the most common chronic infections found in developing countries. Cholesteatoma will stimulate bone resorption from the epithelial and stromal cells resulting in cytokine and keratinocyte formation, as well as mastoid bone destruction. The Ki-67 found in the proliferating cell shows that this protein plays an important role as a cell division process marker. Objective: Analyzing the association of Ki-67 on bone destruction in CSOM with cholesteatoma. Method: Participants in this study were CSOM patients with cholesteatoma who underwent surgery. Participants were assessed for bone destruction based on CT scan examination and confirmed during surgery. Examination of Ki-67 levels was carried out by taking cholesteatoma tissue at the time of surgery and analyzed using the ELISA method. The results of the examination were analyzed using the Spearman's rank correlation, Pearson’s correlation and logistic regression with p < 0.05. Results: The value of Ki-67 levels at each degree of destruction was degree 1 of 0.301, degree 2 of 0.36 ± 0.34, degree 3 of 0.41 ± 0.07, degree 4 of 0.60 ± 0.85, degree 5 of 0.74 ± 0.12, and degree 6 equal to 0.90 (r = 0.906; p = 0.001). In addition, there was a significant relationship between symptoms duration on bone destruction (r = 0.913; p = 0.001) and levels of Ki-67 (r = 0.887; p < 0.001). The regression coefficient was 0.079 for the independent variable, bone destruction with p = 0.009, and the regression coefficient 0.024 for symptoms duration with p = 0.014. Conclusion: Increased Ki-67 level in cholesteatoma is associated with bone destruction degree in CSOM patients with cholesteatoma.

RANKL and RANK in extracellular vesicles: surprising new players in bone remodeling.

Receptor activator of nuclear factor kappa B-ligand (RANKL), its receptor RANK, and osteoprotegerin which binds RANKL and acts as a soluble decoy receptor, are essential controllers of bone remodeling. They also play important roles in establishing immune tolerance and in the development of the lymphatic system and mammary glands. In bone, RANKL stimulates osteoclast formation by binding RANK on osteoclast precursors and osteoclasts. This is required for bone resorption. Recently, RANKL and RANK have been shown to be functional components of extracellular vesicles (EVs). Data linking RANKL and RANK in EVs to biological regulatory roles are reviewed, and crucial unanswered questions are examined. RANKL and RANK are transmembrane proteins and their presence in EVs allows them to act at a distance from their cell of origin. Because RANKL-bearing osteocytes and osteoblasts are often spatially distant from RANK-containing osteoclasts in vivo, this may be crucial for the stimulation of osteoclast formation and bone resorption. RANK in EVs from osteoclasts has the capacity to stimulate a RANKL reverse signaling pathway in osteoblasts that promotes bone formation. This serves to couple bone resorption with bone formation and has inspired novel bifunctional therapeutic agents. RANKL- and RANK- containing EVs in serum may serve as biomarkers for bone and immune pathologies. In summary, EVs containing RANKL and RANK have been identified as intercellular regulators in bone biology. They add complexity to the central signaling network responsible for maintaining bone. RANKL- and RANK-containing EVs are attractive as drug targets and as biomarkers.

TGF-&lt;i&gt;β&lt;/i&gt;1 Stimulates Bone Resorption during Orthodontic Tooth Movement

TGF-&lt;i&gt;β&lt;/i&gt;1 Stimulates Bone Resorption during Orthodontic Tooth Movement

Tumor Necrosis Factor-Alpha and Age-Related Pathologies

Modern concepts about the «inflammaging» and the role of subclinical inflammation in various age-associated pathology are described in the review. Particular attention is paid to the tumor necrosis factor-α, a key cytokine that plays an important role in the pathogenesis of chronic inflammatory diseases as well as in aging. The increased levels of tumor necrosis factor-α leads to the onset and progression of various diseases, to severity of frailty, to disability and mortality of elderly persons. Tumor necrosis factor-α affects different risk factors for cardiovascular diseases, contributes to the onset and progression of atherosclerosis and related pathology. This cytokine can also aggravate various metabolic disorders, mainly — insulin resistance and diabetes mellitus. Tumor necrosis factor-α is a key cytokine that stimulates bone resorption (up to osteoporosis) and sarcopenia (up to cachexia). Currently available data confirm the important role of tumor necrosis factor-α in various age-associated disorders.

Deletion of the proton receptor OGR1 in mouse osteoclasts impairs metabolic acidosis-induced bone resorption

Metabolic acidosis induces osteoclastic bone resorption and inhibits osteoblastic bone formation. Previously we found that mice with a global deletion of the proton receptor OGR1 had increased bone density although both osteoblast and osteoclast activity were increased. To test whether direct effects on osteoclast OGR1 are critical for metabolic acidosis stimulated bone resorption, we generated knockout mice with an osteoclast-specific deletion of OGR1 (knockout mice). We studied bones from three-month old female mice and the differentiated osteoclasts derived from bone marrow of femurs from these knockout and wild type mice. MicroCT demonstrated increased density in tibiae and femurs but not in vertebrae of the knockout mice. Tartrate resistant acid phosphatase staining of tibia indicated a decrease in osteoclast number and surface area/bone surface from knockout compared to wild type mice. Osteoclasts derived from the marrow of knockout mice demonstrated decreased pit formation, osteoclast staining and osteoclast-specific gene expression compared to those from wild type mice. In response to metabolic acidosis, osteoclasts from knockout mice had decreased nuclear translocation of NFATc1, a transcriptional regulator of differentiation, and no increase in size or number compared to osteoclasts from wild type mice. Thus, loss of osteoclast OGR1 decreased both basal and metabolic acidosis-induced osteoclast activity indicating osteoclast OGR1 is important in mediating metabolic acidosis-induced bone resorption. Understanding the role of OGR1 in metabolic acidosis-induced bone resorption will provide insight into bone loss in acidotic patients with chronic kidney disease.

Changes in Bone Metabolism and Structure in Primary Hyperparathyroidism

Abstract Parathyroid hormone (PTH) is a key regulator of bone turnover. Depending on the duration of action, the hormone causes catabolic and anabolic effects by binding with specific receptors (PTHR1) in the bone. Various cells expressing PTHR1 on their surface are involved in the process – osteoblasts, osteocytes, bone marrow stromal cells, T-lymphocytes and macrophages. In physiological conditions PTH balances the bone metabolism. Intermittent pharmacological doses of PTH lead to the prevalence of bone formation and are used in the treatment of osteoporosis. Persistently elevated levels of PTH stimulate bone resorption by impacting mainly the cortical bone. New imaging and analysis techniques show that high PTH levels can also have an adverse effect on trabecular microarchitecture. Primary hyperparathyroidism (PHPT) is a disease characterized by increased bone metabolism, decreased bone mineral density (BMD), inadequate osteoid mineralization and an increased risk of fractures. Prolonged overproduction of PTH leads to stimulation of bone resorption and defects in bone formation, mainly causing loss of cortical bone mass, while in the trabecular bone predominate demineralization processes. One explanation of these findings is the enhanced stimulation of RANKL expression by osteoblasts with decreased OPG expression and bone formation at the same time.

Serum-derived exosomes from neurofibromatosis type 1 congenital tibial pseudarthrosis impaired bone by promoting osteoclastogenesis and inhibiting osteogenesis.

Treatment of congenital pseudarthrosis of the tibia (CPT) still is full of challenges in pediatric orthopedist. Serum-derived exosomes (SDEs) have been proven to be participated in bone remodeling. However, the molecular changes in SDEs of CPT children and their pathologies have not been elucidated. In this study, SDEs were isolated and purified from CPT patients (CPT-SDEs) associated with neurofibromatosis type 1 (NF1) and normal children (Norm-SDEs). Then we obtained the proteomics profile of SDEs by combining liquid chromatography-tandem mass spectrometry (LC-MS/MS) and tandem mass tag label-based quantitation. In vitro, the efficacy of SDEs on osteoblastic differentiation of MC3T3-E1 cells and osteoclastogenesis ability of RAW264.7 cells were evaluated by quantitative real-time PCR (qRT-PCR) and cytochemical staining. In vivo, we used micro-CT to assess cortical bone mass and trabecular microstructures to reflect the influence of SDEs on bone remodeling after injection into the tail vein of rats. Based on proteomics analysis, 410 differentially expressed proteins, including 289 downregulated proteins and 121 upregulated proteins, were identified in the CPT-SDEs. These proteins have multiple biological functions associated with cellular metabolic processes, catalytic activity, and protein binding, which are important for cell differentiation and proliferation. In vitro, CPT-SDEs decreased the osteogenic differentiation of MC3T3-E1 cells and promoted the osteoclastogenesis of RAW264.7 cells. Injection of CPT-SDEs into the tail vein for two months resulted in bone loss in rats, as indicated by the decrease in trabecular and cortical bone mass. Our findings demonstrated the differences in proteins in SDEs between normal and CPT children with NF1. These differentially expressed proteins in CPT-SDEs contributed to deteriorating trabecular bone microstructures by inhibiting bone formation and stimulating bone resorption.

The Vitamin D Receptor in Osteoblast-Lineage Cells Is Essential for the Proresorptive Activity of 1α,25(OH)2D3 In Vivo.

We previously reported that daily administration of a pharmacological dose of eldecalcitol, an analog of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], increased bone mass by suppressing bone resorption. These antiresorptive effects were found to be mediated by the vitamin D receptor (VDR) in osteoblast-lineage cells. Using osteoblast-lineage-specific VDR conditional knockout (Ob-VDR-cKO) mice, we examined whether proresorptive activity induced by the high-dose 1α,25(OH)2D3 was also mediated by VDR in osteoblast-lineage cells. Administration of 1α,25(OH)2D3 (5 μg/kg body weight/day) to wild-type mice for 4 days increased the number of osteoclasts in bone and serum concentrations of C-terminal crosslinked telopeptide of type I collagen (CTX-I, a bone resorption marker). The stimulation of bone resorption was concomitant with the increase in serum calcium (Ca) and fibroblast growth factor 23 (FGF23) levels, and decrease in body weight. This suggests that a toxic dose of 1α,25(OH)2D3 can induce bone resorption and hypercalcemia. In contrast, pretreatment of wild-type mice with neutralizing anti-receptor activator of NF-κB ligand (RANKL) antibody inhibited the 1α,25(OH)2D3-induced increase of osteoclast numbers in bone, and increase of CTX-I, Ca, and FGF23 levels in serum. The pretreatment with anti-RANKL antibody also inhibited the 1α,25(OH)2D3-induced decrease in body weight. Consistent with observations in mice conditioned with anti-RANKL antibody, the high-dose administration of 1α,25(OH)2D3 to Ob-VDR-cKO mice failed to significantly increase bone osteoclast numbers, serum CTX-I, Ca, or FGF23 levels, and failed to reduce the body weight. Taken together, this study demonstrated that the proresorptive, hypercalcemic, and toxic actions of high-dose 1α,25(OH)2D3 are mediated by VDR in osteoblast-lineage cells.

Focus on the Multimodal Role of Autophagy in Rheumatoid Arthritis.

Autophagy exerts its dual role in eukaryotic cells and exerts its cytoprotective action through degradation mechanism and by regulating catabolic processes which results in elimination of pathogens. Under suitable conditions, autophagy is associated with recycling of cytoplasmic components which causes regeneration of energy whereas deregulated autophagy exerts its implicated role in development and pathogenesis of auto-immune diseases such as rheumatoid arthritis. The immune, innate, and adaptive responses are regulated through the development, proliferation, and growth of lymphocytes. Such innate and adaptive responses can act as mediator of arthritis; along with this, stimulation of osteoclast-mediated bone resorption takes place via transferring citrullinated peptides towards MHC (major histocompatibility complex) compartments, thereby resulting in degradation of bone. Processes such as apoptosis resistance are also regulated through autophagy. In this review, the current knowledge based on role of autophagy in pathogenesis of rheumatoid arthritis is summarized along with proteins associated.

Skeletal health in patients with differentiated thyroid carcinoma.

Osteoporosis and fractures are important comorbidities in patients with differentiated thyroid cancer (DTC), with potential negative impact on quality of life and survival. The main determinant of skeletal fragility in DTC is the thyrotropin (TSH)-suppressive therapy, which is commonly recommended to prevent disease's recurrence, especially in patients with structural incomplete response after thyroid surgery and radio-iodine therapy. TSH-suppressive therapy can stimulate bone resorption with consequent bone loss, deterioration of bone microstructure and high risk of fragility fractures. The skeletal effects of TSH-suppressive therapy may be amplified when thyroid cancer cells localize to the skeleton inducing alterations in bone remodelling, impairment of bone structure and further increase in risk of fractures. The management of skeletal fragility in DTC may be challenging, since prediction of fractures is a matter of uncertainty and data on effectiveness and safety of bone-active agents in this clinical setting are still scanty. This review deals with pathophysiological, clinical and therapeutic aspects of skeletal fragility of patients with DTC.

Increased Osteoblastic Cxcl9 Contributes to the Uncoupled Bone Formation and Resorption in Postmenopausal Osteoporosis.

IntroductionEstrogen deficiency leads to bone loss in postmenopausal osteoporosis, because bone formation, albeit enhanced, fails to keep pace with the stimulated osteoclastic bone resorption. The mechanism driving this uncoupling is central to the pathogenesis of postmenopausal osteoporosis, which, however, remains poorly understood. We previously found that Cxcl9 secreted by osteoblasts inhibited osteogenesis in bone, while the roles of Cxcl9 on osteoclastic bone resorption and osteoporosis are unclear.Materials and MethodsPostmenopausal osteoporosis mouse model was established by bilateral surgical ovariectomy (OVX). In situ hybridization was performed to detect Cxcl9 mRNA expression in bone. ELISA assay was conducted to assess Cxcl9 concentrations in bone and serum. Cxcl9 activity was blocked by its neutralizing antibody. Micro-CT was performed to determine the effects of Cxcl9 neutralization on bone structure. Cell Migration and adhesion assay were conducted to evaluate the effects of Cxcl9 on osteoclast activity. TRAP staining and Western blot were performed to assess osteoclast differentiation. CXCR3 antagonist NBI-74,330 or ERK antagonist SCH772984 was administered to osteoclast to study the effects of Cxcl9 on CXCR3/ERK signaling.ResultsCxcl9 was expressed and secreted increasingly in OVX mice bone. Neutralizing Cxcl9 in bone marrow prevented bone loss in the mice by facilitating bone formation as well as inhibiting bone resorption. In vitro, Cxcl9 secreted from osteoblasts facilitated osteoclast precursors adhesion, migration and their differentiation into mature osteoclasts. The positive role of osteoblastic Cxcl9 on osteoclasts was eliminated by blocking CXCR3/ERK signaling in osteoclasts. Estrogen negatively regulated Cxcl9 expression and secretion in osteoblasts, explaining the increased Cxcl9 concentration in OVX mice bone.ConclusionOur study illustrates the roles of Cxcl9 in inhibiting bone formation and stimulating bone resorption in osteoporotic bone, therefore providing a possible therapeutic target to the treatment of postmenopausal osteoporosis.