Non-POEMS osteosclerotic multiple myeloma: Clinical characteristics and differential diagnosis.

Osteosclerosis in multiple myeloma (MM) is typically associated with rare POEMS syndrome, characterized by polyneuropathy (P), organomegaly (O), endocrinopathy (E), M-protein (M), and skin changes (S). However, osteosclerosis in multiple myeloma (MM) without POEMS syndrome, defined as non-POEMS Osteosclerotic MM, is exceedingly rare. We report a 70-year-old man with rib pain, remarkably high bone mineral density and diffuse osteosclerosis. The diagnosis of non-POEMS osteosclerotic MM was confirmed by biopsy and aspiration of bone marrow through surgery. A literature review spanning from 1990 identified 12 cases of similar non-POEMS osteosclerotic MM, including 5 males and 7 females with a mean age of 59.7 ± 10.6 years. The non-POEMS osteosclerotic MM can be divided into two subtypes, the osteosclerotic lesion subtype and the diffuse osteosclerosis subtype. Absence of polyneuropathy and organomegaly are the main factors that differentiate non-POEMS osteosclerotic MM from POEMS. A hyperactive osteoblastic process might be the etiology of diffuse osteosclerosis. Further research is needed to understand its etiology and pathophysiology.

Knowledge, attitude, and practice regarding sarcopenia: a survey between orthopedic and geriatric professionals in China.

BACKGROUND: In elderly patients with fractures, sarcopenia impairs recovery and even increases mortality. Both orthopedic and geriatric professionals are at the forefront of treating sarcopenic patients with fractures. However, it is not clear to what extent they have knowledge and skills to diagnose and treat sarcopenia. AIMS: This study aimed to analyze and compare knowledge, attitude, and practice regarding sarcopenia between orthopedic and geriatric professionals. METHODS: An online cross-sectional survey was conducted in June 2022 targeting professionals in orthopedic and geriatric departments in two largest tertiary general hospitals in Taizhou, southeastern China. Results on knowledge, attitude, and practice of sarcopenia were analyzed. Variables with significance were then included in a stepwise multiple linear regression analysis. RESULTS: A total of 220 professionals, 176 from orthopedic departments and 44 from geriatric departments, participated in this study. Orthopedic professionals scored lower than geriatrics in knowledge, attitude and practice (P < 0.001). The attitude score was high in both orthopedic and geriatric professionals. Stepwise multiple linear regression analysis showed that participants who had contact with sarcopenia patients had higher knowledge score (ß = 1.941, P < 0.001); participants who had attended sarcopenia training in the past 6 months (ß = 4.305, P < 0.001) had higher practice score. DISCUSSION: Orthopedic professionals have deficiencies in the screening and diagnosis of sarcopenia. Improving the knowledge and training of professionals can strengthen practice. It is necessary to formulate diagnostic criteria and improve practice of sarcopenia through training. CONCLUSION: Orthopedic professionals had limited knowledge and practice regarding sarcopenia compared with geriatric professionals. To improve sarcopenia practice, the use of diagnostic tools to formally diagnose sarcopenia and regular training on sarcopenia should be encouraged.

EGFL6 promotes bone metastasis of lung adenocarcinoma by increasing cancer cell malignancy and bone resorption.

Lung adenocarcinoma is the most common and aggressive type of lung cancer with the highest incidence of bone metastasis. Epidermal growth factor-like domain multiple 6 (EGFL6) is an exocrine protein, and the expression of EGFL6 is correlated with survival of patient with lung adenocarcinoma. However, the association between EGFL6 expression in lung adenocarcinoma and bone metastasis has not been investigated. In this study, we found that EGFL6 levels in lung adenocarcinoma tissues correlate with bone metastasis and TNM stages in surgical patients. In vitro, overexpression of EGFL6 in lung adenocarcinoma cells promoted their proliferation, migration, and invasion ability compared with control by enhancing EMT process and activating Wnt/ß-catenin and PI3K/AKT/mTOR pathways. In the nude mouse model, overexpression of EGFL6 enhanced tumor growth and caused greater bone destruction. Moreover, the exocrine EGFL6 of human lung adenocarcinoma cells increased osteoclast differentiation of bone marrow mononuclear macrophages (BMMs) of mice via the NF-κB and c-Fos/NFATc1 signaling pathways. However, exocrine EGFL6 had no effect on osteoblast differentiation of bone marrow mesenchymal stem cells (BMSCs). In conclusion, high expression of EGFL6 in lung adenocarcinomas is associated with bone metastasis in surgical patients. The underlying mechanism may be the increased metastatic properties of lung adenocarcinoma cells with high EGFL6 level and the enhanced osteoclast differentiation and bone resorption by exocrine EGFL6 from tumors. Therefore, EGFL6 is a potential therapeutic target to reduce the ability of lung adenocarcinomas to grow and metastasize and to preserve bone mass in patients with bone metastases from lung adenocarcinomas.

Denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women: A randomized, double-blind, placebo-controlled, multicenter phase III study.

Objectives: This study assessed the efficacy, safety, pharmacokinetics (PK), and immunogenicity profiles of a denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women with a high risk of fracture. Methods: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, 448 postmenopausal women aged 50-85 years with osteoporosis were enrolled at 49 centers in China and were randomly assigned (3:1) to receive 60 â€‹mg of the denosumab biosimilar (LY06006) or placebo subcutaneously every 6 months for 1 year. Lumbar spine bone mineral density (BMD) change was the primary endpoint. Results: Of the 448 randomized patients, 409 (LY06006, n â€‹= â€‹311; placebo, n â€‹= â€‹98) completed the study. All 448 (100.0%) subjects were included in the intent-to-treat (ITT) trial, 427 (95.3%) were included in the full analysis set (FAS), 408 (91.1%) were included in the per protocol set (PPS), 446 (99.6%) were included in the safety set (SS), and 336 (75.0%) were included in the pharmacokinetics concentration set (PKCs). For the primary endpoint, a 4.71% (95% CI, 3.81%, 5.60%) treatment difference in percent change in lumbar spine BMD from baseline to month 12 was observed in the LY06006 group compared with the placebo group (P â€‹< â€‹0.0001). For the secondary endpoints, LY06006 was associated with increased lumbar spine BMD levels measured at month 6, BMD levels at the femoral neck, total hip, and trochanter measured at months 6 and 12 and reduced serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 â€‹N-peptide (P1NP) levels at months 1, 6, and 12. Safety analysis was based on the safety analysis set (SS), and 264 (78.6%) subjects in the LY06006 group and 83 (75.5%) in the placebo group experienced adverse events (AEs). Most events were mild or moderate and not related to the study drugs. Conclusion: In postmenopausal women with a high risk of fracture, LY06006 increased the BMD and decreased bone resorption; thus, LY06006 might be an effective treatment for osteoporosis. LY06006 was generally safe and well tolerated without unexpected adverse reactions, similar to the reference drug Prolia®. The characteristics of effectiveness and safety were similar to those reported in previous studies. The translational potential of this article: In this multi-center, randomized, double-blind, placebo-controlled phase 3 study, LY06006 showed substantially efficacy to increase BMD and well tolerance without unexpected adverse reactions, which is comparable to the reference drug Prolia ®. The presented results are encouraging and can offer some valuable evidence for the clinical practice.

Is spinal sagittal alignment of diffuse idiopathic skeletal hyperostosis relevant to thoracolumbar pain? A controlled study.

OBJECTIVES: The extension of diffuse idiopathic skeletal hyperostosis (DISH) from the low thoracic spine to the lumbar spine result in adjustment of spinal sagittal alignment in surgical patients. The aim of this study was to investigate changes in sagittal alignment and back pain in the thoracolumbar spine in nonsurgical DISH and control participants selected from a radiological database. METHODS: Participants in the DISH and the control group were selected by searching for "DISH or degenerative changes in the thoracic spine" in the radiology database of Taizhou Hospital between 2018 and 2021 using Resnick and Niwayama's criteria. The subjects with spinal tumors, previous spinal surgery, vertebral fractures, inflammatory diseases, poor-quality radiographs, or loss of follow-up were excluded. Demographic and clinical characteristics were recorded retrospectively via the hospital information system and telephone follow-up. Segmental disc angles (SDAs), lumbar lordosis (LL), and bridge scores were analyzed using images of three-dimensional CT. RESULTS: The final participants consisted of 51 individuals with DISH (DISH group) and 102 individuals without DISH (control group). Depending on the presence of thoracolumbar pain, the DISH group was divided into the DISH group with thoracolumbar pain (DISH+Pain) and the DISH group without thoracolumbar pain (DISH-Pain). The LL and SDAs of T11-T12 and T12-L1 were significantly greater in the DISH group than in the control group. In addition, the SDA of L1-L2 was significantly smaller in the DISH+Pain group than in the DISH-Pain group, whereas there was no significant difference in lumbar lordosis between the DISH+Pain group and the DISH-Pain group. The bridge scores in DISH+Pain group was larger in T10-T11 (p = 0.01) and L1-L2 (p < 0.01) spine segments than those in DISH-Pain group. CONCLUSION: The extension of DISH from thoracic to lumbar spine may increase lumbar lordosis and SDAs in the thoracolumbar spine. The DISH patients with more bony bridging and small L1-L2 SDA may be more likely have thoracolumbar pain. Adjustment of sagittal alignment of the spine in the development of DISH may be of clinical importance.

Acyloxyacyl hydrolase deficiency induces chronic inflammation and bone loss in male mice.

Hormonal homeostasis is essential in bone remodeling. Recent studies have shown that the treatment of intestinal inflammation can result in the regulation of bone resorption in distant bones. Increased intestinal permeability may lead to systemic inflammation and bone loss, also known as gut-bone axis. However, the underlying mechanism remains to be elucidated. Lipopolysaccharide (LPS) is a component of gram-negative bacteria that can increase osteoclastic differentiation in vitro. Acyloxyacyl hydrolase (AOAH) is a specific degrading enzyme of LPS, but little is known about the role of AOAH in bone metabolism. In this study, adult Aoah-/- mice showed a chronic inflammatory state and osteopenic phenotype analyzed by micro-CT and HE staining. Tartrate-resistant acid phosphatase (TRAP) staining of femurs showed an increase in TRAP-positive cells from Aoah-/- mice. AOAH depletion enhanced the osteoclast differentiation and bone resorption capacity of bone marrow-derived macrophages (BMMs). The enhanced osteoclast differentiation and bone resorption capacity of Aoah-/- BMMs were reversed by rAOAH. In conclusion, the chronic inflammatory state of adult Aoah-/- mice promotes bone resorption. AOAH participates in bone metabolism, which is mainly mediated by inhibiting osteoclast differentiation. LPS may be a key mediator of the gut-bone axis, and targeting AOAH may represent a feasible strategy for the treatment of chronic inflammatory bone resorption. KEY MESSAGES : AOAH knockout mice exhibited chronic inflammation mediated by LPS, and LPS may also serve as an important mediator in the regulation of bone metabolism in the gut-bone axis. AOAH regulated bone resorption by blocking the osteoclast differentiation via classical ERK and JNK pathways. rAOAH could rescue the enhanced osteoclast differentiation caused by AOAH deficiency.

Association of Helicobacter pylori infection with osteoporosis risk in a physical examination population.

The association between Helicobacter pylori (H. pylori) infection and osteoporosis risk remains equivocal. Our findings showed that H. pylori infection appears to have no effect on the risk of osteopenia and osteoporosis. Weight status may modify the association of H. pylori infection with low bone mass. PURPOSE: To evaluate the association between baseline H. pylori infection and osteoporosis risk in the general population. METHODS: From January 1, 2019, to March 31, 2020, 1388 women and men aged over 50 years underwent a health examination. H. pylori infection was detected by the 13C urea breath test. Subjects were classified as having normal bone mineral density (BMD), osteopenia, and osteoporosis according to dual-energy X-ray absorptiometry. Chi-square tests and multinomial logistic regression models were performed to analyze the associations of H. pylori infection with osteopenia and osteoporosis. RESULTS: Of the 1388 participants, 545 (39.3%) were H. pylori-positive. The prevalence rates of osteoporosis and osteopenia were 10.2% and 32.3%, respectively. No differences were observed in the rates of osteoporosis and osteopenia between H. pylori-positive and H. pylori-negative groups (P > 0.05). The association for the trend between the H. pylori infection and osteoporosis was only seen in the nonoverweight subgroup (trend χ2 = 5.455, P = 0.02). The odds ratio (OR) between H. pylori infection and osteoporosis was 1.31 (95% CI, 0.86-2.02, P = 0.211) after adjusting for sex, age, and body weight status. CONCLUSIONS: We demonstrate that H. pylori infection is not an independent risk factor for osteopenia and osteoporosis. This study did not support the association of H. pylori infection with osteoporosis.

Effect of Acute Limb Ischemia on the Mortality of Patients with Extracorporeal Membrane Oxygenation Established by Femoral Vein-Arterial Catheterization and Analysis of Related Risk Factors.

Extracorporeal membrane oxygenation (ECMO) is a common treatment for cardiopulmonary failure. Although it can effectively reduce the mortality of patients with cardiopulmonary failure, it still has a high mortality rate, such as acute limb ischemia (ALI), stroke, liver and kidney failure, and other related complications and related causes of death. This study aims to explore the impact of ALI on the mortality of VA-ECMO patients in hospital and 6 months after discharge and analyze the occurrence of ALI and related factors that affect the mortality of VA-ECMO in hospital and 6 months after discharge. The results showed that the smoking history was an independent risk factor for ALI, and age, diabetes, cardiac arrest, first time of ECMO, and hyperbilirubinemia were associated risk factors for in-hospital mortality. Cardiac arrest and ALI were associated risk factors for mortality at 6 months after discharge. Although ALI is not significantly associated with VA-ECMO in-hospital mortality, it is a risk factor for mortality at 6 months after discharge, and medical personnel should therefore strive to reduce and avoid ALI.

A modified tape transfer approach for rapidly preparing high-quality cryosections of undecalcified adult rodent bones.

BACKGROUND/OBJECTIVE: Histology-based analyses are important tools to dissect cellular and molecular mechanisms of skeletal homeostasis, diseases, and regeneration. The success of these efforts is highly dependent on rapidly obtaining high-quality sections of mineralized skeletal tissues suitable for various analyses. However, the current techniques for preparing such sections are still far from satisfactory. This study aimed to develop a new approach for preparing high-quality undecalcified bone sections applicable to various histological analyses. METHODS: Two important modifications were made to the conventional Cryojane Tape-Transfer System, including utilization of an optimized adhesive to prepare adhesive glass slides for improving the transfer efficiency, and a cheap conventional benchtop UV transilluminator for UV curing. Cryosections of undecalcified rodent bones were prepared using this modified tape transfer approach, and their tissue morphology and structural integrity were visually examined. A variety of histological analyses, including calcein labeling, Von kossa staining, immunofluorescence, and enzymatic activity staining as well as 5-Ethynyl-2'-deoxyuridine (EdU) and TUNEL assays, were performed on these sections. RESULTS: We developed a modified version of tape transfer approach that can prepare cryosections of undecalcified rodent adult bones within 4 days at a low cost. Bone sections prepared by this approach exhibited good tissue morphology and structural integrity. Moreover, these sections were applicable to a variety of histological analyses, including calcein labeling, Von kossa staining, immunofluorescence, and enzymatic activity staining as well as EdU and TUNEL assays. CONCLUSION: The tape transfer approach we developed provides a rapid, affordable, and easy learning method for preparing high-quality undecalcified bone sections valuable for bone research. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: Our research provides a rapid, affordable, and easy learning method for preparing high-quality undecalcified bone sections that can be potentially used for accurate diagnosis of various bone disorders and evaluation of the efficacy of different therapies in the treatment of these diseases.

Association between the metabolome and bone mineral density in a Chinese population.

BACKGROUND: Osteoporosis is a common metabolic bone disease, which always leads to osteoporotic fractures. Biomarkers of bone mineral density (BMD) are helpful for prevention and early diagnosis of osteoporosis. This study aims to identify metabolomic biomarkers of low BMD. METHODS: We included 701 participants who had BMD measures by dual-energy X-ray absorptiometry scans and donated fasting plasma samples from three clinical centres as a discovery set and another 278 participants from the fourth centre as an independent replication set. We used a liquid chromatography-mass spectrometry-based metabolomics approach to profile the global metabolites of fasting plasma. FINDINGS: Among the 265 named metabolites identified in our study, six were associated with low BMD (FDR-adjusted P<0.05) in the discovery set and were successfully validated in the independent replication set. The circulating levels of five metabolites, i.e., inosine, hypoxanthine, PC (O-18:0/22:6), SM (d18:1/21:0) and isoleucyl-proline were associated with decreased odds of low BMD, and PC (16:0/18:3) level was associated with increased odds of low BMD. Per 1-SD increase in a composite metabolite score of these six metabolites was associated with about half decreased odds of low BMD (odds ratio 0.59, 95% confidence interval: 0.52-0.68). Furthermore, introduction of a panel of metabolites selected by elastic net regression to a prediction model of classical risk factors and plasma biomarker of bone resorption substantially improved the prediction performance for low BMD (AUCs: 0.782 vs. 0.698, P=0.002). INTERPRETATION: Metabolomics profiling may help identify novel biomarkers of low BMD and be helpful for early diagnosis of osteoporosis beyond the current clinical index. FUNDING: This study was supported by the National Key R&D Program of China [2018YFC2001500 to J.S.], Shanghai Municipal Science and Technology Major Project [2017SHZDZX01], the National Natural Science Foundation of China [Key Program, 91749204 to J.S.], the National Natural Science Foundation of China [General Program, 81771491 to J.S.], the Project of Shanghai Subject Chief Scientist [2017BR011 to J.S.], Grants from the TCM Supported Project [18431902300 to J.S.] from the Science and Technology Commission of Shanghai Municipality, and the National Natural Science Foundation of China [General Program, 81972089 to Z.X.]. Y.Z. was supported by the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and the National Natural Science Foundation of China [81973032].

Nepetin inhibits osteoclastogenesis by inhibiting RANKL-induced activation of NF-κB and MAPK signalling pathway, and autophagy.

Aseptic prosthetic loosening due to wear particle-induced inflammatory osteolysis is the main cause of failure for artificial joint replacement. The inflammatory response and the production of pro-osteoclastic factors lead to elevation of osteoclast formation and excessive activity results in extensive bone destruction around the bone-implant interface. Here we showed that Nepetin, a natural bioactive flavonoid with proven anti-inflammatory and anti-proliferative properties, potently inhibited RANKL-induced osteoclast differentiation, formation and bone resorption in vitro, and protected mice against the deleterious effects of titanium particle-induced calvarial osteolysis in vivo. Mechanistically, Nepetin attenuated RANKL-induced activation of NF-κB and MAPK signalling pathways and TRAF6-dependent ubiquitination of Beclin 1 which is necessary for the induction of autophagy. In brief, our study demonstrates the potential therapeutic application of Nepetin against osteoclast-mediated osteolytic diseases.

Psoas hematoma as a rare complication of posterior lumbar interbody fusion: a case report.

BACKGROUND: Psoas hematoma rarely occurs in patients with spondylolisthesis who undergo posterior lumbar interbody fusion (PLIF) surgery. CASE PRESENTATION: Here we reported a case of a 57-year-old male patient diagnosed with spondylolisthesis who underwent PLIF at the local hospital. Seven days post-surgery, abdominal pain occurred, and the pain in the right lower limb gradually increased. The computerized tomography (CT) indicated a formation of hematoma around the psoas muscle. Digital-subtraction angiography (DSA) suggested a vascular injury, a rupture of the right segmental artery of the lumbar vertebral level 4. The patient then received DSA vascular embolization, after which the lower lumbar segmental artery active bleeding was stopped. One month after discharge, the abdominal hematoma was gradually absorbed, and the pain in the waist, leg, and abdomen disappeared. CONCLUSION: Symptoms such as abdominal pain, abdominal distension, and exacerbation of lower limb pain, may suggest the occurrence of psoas hematoma after PLIF. DSA vascular embolization is suggested as the first treatment approach for this type of complication.

Genetic and pharmacological activation of Hedgehog signaling inhibits osteoclastogenesis and attenuates titanium particle-induced osteolysis partly through suppressing the JNK/c-Fos-NFATc1 cascade.

Rationale: Wear particle-induced periprosthetic osteolysis (PPO) is a common long-term complication of total joint arthroplasty, and represents the major cause of aseptic loosening and subsequent implant failure. Previous studies have identified the central role of osteoclast-mediated bone resorption in the pathogenesis of PPO. Thus, therapeutic approaches of inhibiting osteoclast formation and activity are considered to be of great potential to prevent and treat this osteolytic disease. Hedgehog (Hh) signaling has been shown to play an important role in promoting osteoblast differentiation and bone formation. While Hh signaling is also implicated in regulating osteoclastogenesis, whether it can directly inhibit osteoclast differentiation and bone resorption remains controversial. Moreover, its potential therapeutic effects on PPO have never been assessed. In this study, we explored the cell-autonomous role of Hh signaling in regulating osteoclastogenesis and its therapeutic potential in preventing wear particle-induced osteolysis. Methods: Hh signaling was activated in macrophages by genetically ablating Sufu in these cells using LysM-Cre or by treating them with purmorphamine (PM), a pharmacological activator of Smoothened (Smo). In vitro cell-autonomous effects of Hh pathway activation on RANKL-induced osteoclast differentiation and activity were evaluated by TRAP staining, phalloidin staining, qPCR analyses, and bone resorption assays. In vivo evaluation of its therapeutic efficacy against PPO was performed in a murine calvarial model of titanium particle-induced osteolysis by µCT and histological analyses. Mechanistic details were explored in RANKL-treated macrophages through Western blot analyses. Results: We found that Sufu deletion or PM treatment potently activated Hh signaling in macrophages, and strongly inhibited RANKL-induced TRAP+ osteoclast production, F-actin ring formation, osteoclast-specific gene expression, and osteoclast activity in vitro. Furthermore, we found that Sufu deletion or PM administration significantly attenuated titanium particle-induced osteoclast formation and bone loss in vivo. Our mechanistic study revealed that activation of Hh signaling suppressed RANKL-induced activation of JNK pathway and downregulated protein levels of two key osteoclastic transcriptional factors, c-Fos and its downstream target NFATc1. Conclusions: Both genetic and pharmacological activation of Hh signaling can cell-autonomously inhibit RANKL-induced osteoclast differentiation and activity in vitro and protect against titanium particle-induced osteolysis in vivo. Mechanistically, Hh signaling hinders osteoclastogenesis partly through suppressing the JNK/c-Fos-NFATc1 cascade. Thus, Hh signaling may serve as a promising therapeutic target for the prevention and treatment of PPO and other osteolytic diseases.

Neferine suppresses osteoclast differentiation through suppressing NF-κB signal pathway but not MAPKs and promote osteogenesis.

Osteoporosis is an ageing disease characterized by elevated osteoclastic bone resorption resulting in bone loss, decrease bone strength, and elevated incidence of fractures. Neferine, a natural compound isolated from the traditional Chinese medicine Nelumbo nucifera (Lotus), has been reported exhibit anti-inflammatory, antioxidant, and anticancer properties. However, its effect on bone remains to be determined. Here we showed that Neferine inhibits RANKL-induced osteoclast formation in a dose- and time-dependent manner. Furthermore, Neferine also demonstrated antiresorptive properties by effectively ameliorating the bone resorptive activity of mature osteoclasts. Mechanistically, Neferine suppressed RANKL-induced activation of NF-κB signaling pathway. This in turn hindered the induction and activation of NFATc1 resulting in downregulation of osteoclast marker genes closely related to differentiation, fusion as well as bone resorption. Interestingly, we found Neferine enhanced the differentiation and bone mineralization activity of MC3T3-E1 preosteoblast cells. Finally, mice treated with Neferine was protected against ovariectomy (OVX)-induced bone loss. The Neferine treatment improved bone volume following ovariectomy and also exhibited less TRAP-positive osteoclasts on bone surface. Collectively our data provide promising evidence that Neferine could be a potential therapeutic application for against osteolytic bone conditions such as osteoporosis.

Histone deacetylase inhibitor CI-994 inhibits osteoclastogenesis via suppressing NF-κB and the downstream c-Fos/NFATc1 signaling pathways.

[4-(acetylamino)-N-(2-amino-phenyl) benzamide] (CI-994) is a histone deacetylase 1-3 specific inhibitor that has been shown to indirectly increase the production of Dickkopf-1, which is an inhibitor of osteoclastic development. However, whether CI-994 has an influence on receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis is still unclear; in our study, this mechanism was investigated. In an in vitro study, using a tartrate-resistant acid phosphatase (TRAP) stain, an F-actin ring, bone absorption test, quantitative PCR and Western blotting, the role of CI-994 in osteoclastogenesis and the expression of related genes and proteins were investigated. In an in vivo study, the effect of CI-994 on osteolysis was evaluated using a titanium particle-induced murine calvarial osteolysis model. Our results indicated that CI-994 inhibited osteoclast differentiation and the function of bone resorption without cytotoxic effects. Moreover, CI-994 inhibited the expression of osteoclast-related genes, including ACP5, CTSK, NFATc1, c-Fos, DC-STAMP and V-ATPase-d2. Furthermore, CI-994 suppressed the phosphorylation of IκBα and p65 and the expression of downstream c-Fos and NFATc1. Consistent with the in vitro results described above, our in vivo experiment indicated that CI-994 inhibited Ti-induced osteolysis. In conclusion, CI-994 inhibited osteoclastogenesis by suppressing NF-κB and the downstream c-Fos/NFATc1 signaling pathway. Thus, this study showed the possibility of using CI-994 for the treatment of exorbitant osteoclastic bone resorption.

Meta-analysis of correlationship between HLA-G 3'UTR 14-bp Ins/Del polymorphism and virus susceptibility.

BACKGROUND: There is a considerable amount of literature on the potential relationship between human leukocyte antigen-G 14-bp Ins/Del polymorphism and virus infection; however, results from these studies were inconclusive. OBJECTIVES: A meta-analysis was carried out to determine whether the 14-bp Ins/Del polymorphism is a susceptible factor for virus infection. METHODS: Data were extracted from PubMed and Web of Science databases, and included 10 case-control studies (1835 patients and 2357 controls). RESULTS: A total of 177 records from 10 studies were retrieved. Overall, no significant correlation was found between HLA-G 14-bp Ins/Del polymorphism and total viruses under all genetic models (dominant model: OR = 0.93, 95% CI = 0.68-1.29; recessive model: OR = 1.12, 95% CI = 0.84-1.48; deletion/deletion (DD) vs insertion/insertion (II): OR = 1.03, 95% CI = 0.71-1.49; deletion (D) vs insertion (I): OR = 1.01, 95% CI = 0.81-1.25). However, further subgroup analyses by virus type and ethnicity revealed that HLA-G 14-bp Ins/Del polymorphism was significantly associated with HTLV-1 infection in mixed population under the dominant model. CONCLUSIONS: Our study demonstrated that HLA-G 14-bp Ins/Del polymorphism may not have any effect on susceptibility to viruses.

Bulleyaconitine A prevents Ti particle-induced osteolysis via suppressing NF-κB signal pathway during osteoclastogenesis and osteoblastogenesis.

Balanced bone resorption and bone formation are vital for bone homeostasis. Excessive osteoclastic bone resorption in this process can cause a variety of bone disorders including osteoporosis, aseptic prosthetic loosening and tumor associated bone destruction. Bulleyaconitine A (BLA) is a natural compound that has been widely used for pain treatment but its role in osteolysis has not yet been investigated. In this study, we verified for the first time that BLA inhibited osteoclast formation, the mRNA expression of osteoclast-related genes and osteoclastic bone resorption by inhibiting NF-κB signal pathway and downstream NFATc1 expression. Meanwhile, BLA had a stimulatory effect in osteoblast differentiation and mineralization. Furthermore, BLA showed preventive effect in Ti particle-induced osteolysis model in vivo. Together, all our data demonstrated that BLA suppressed osteoclastogenesis and promoted osteoblastogenesis via suppressing NF-κB signal pathway and could be an alternative therapeutic choice against bone loss.

Corrigendum: Dihydroartemisinin prevents breast cancer-induced osteolysis via inhibiting both breast cancer cells and osteoclasts.

This corrects the article DOI: 10.1038/srep19074.

Inhibition of heat shock protein 90 rescues glucocorticoid-induced bone loss through enhancing bone formation.

Endogenous glucocorticoids (GCs) support normal bone development and bone mass maintenance, whereas long-term exposure to pharmacological dosages of GCs uncouples bone formation and resorption, resulting in GC-induced osteoporosis (GIOP). Heat shock protein 90 (HSP90) chaperoning glucocorticoid receptor (GR) signaling prompts us to speculate that HSP90 plays critical roles in GC-mediated bone formation and GIOP. In the present study, inhibition of HSP90 activity by 17-Demethoxy-17-allyaminogeldanmycin (17-AAG) or knockdown of HSP90 expression by siRNAs attenuated dexamethasone(Dex)-induced GR nuclear accumulation and transcriptional output of GR signaling, whereas overexpression of HSP90α or HSP90ß enhanced GR transactivity in C3H10T1/2 cells. Though 17-AAG itself enhanced osteoblastic differentiation, it restored the Dex(10-8M)-induced and Dex(10-6M)-negated osteoblastic differentiation in C3H10T1/2 cells and primary calvarial osteoblasts. Moreover, systemic administration of 17-AAG to mice induced not only osteoclastogenesis but also osteoblastogenesis, whereas bone formation possibly exceeded bone resorption, eventually leading to the increased bone masses. Likewise, systemic administration of 17-AAG to mice restored GC-negated osteoblastogenesis and enhanced GC-induced osteoclastogenesis, similarly, 17-AAG-induced bone formation possibly exceeded both 17-AAG- and GC-induced bone resorption, eventually resulting in rescue of GIOP. Together, the present study has revealed that inhibition of HSP90 restores GIOP through enhancing bone formation, and our findings may help to shed light on the pathogenesis of GIOP and provide targets for the therapeutic intervention of the disease.