High-mobility group box chromosomal protein-1 deletion alleviates osteoporosis in OVX rat model via suppressing the osteoclastogenesis and inflammation.

BACKGROUND: Osteoporosis is a skeletal metabolic disease that constitutes a great threaten to human health. However, there is currently no gold standard for its treatment. High-mobility group box chromosomal protein-1 (HMGB-1) has been reported to play an important role in various orthopedic diseases. Till now, its role in osteoporosis remains elusive. METHODS: Rats underwent ovariectomy (OVX) were used to construct a postmenopausal model of osteoporosis. Then, rats were divided into sham groups without OVX surgery, OVX model group, HMGB-1 knockdown (HMGB-1 KD) OVX model groups. The expression of HMGB1 was evaluated by qRT-PCR and western blotting. Subsequently, the changes of trabeculae were evaluated by micro-computed tomography (CT) assay. Skeletal necrosis and metabolism were further analyzed by hematoxylin-eosin (HE) staining, Alcian blue staining and Masson's trichrome staining. The contents of serum alkaline phosphatase (ALP) and osteocalcin were detected by ELISA assay. Expression of osteoclast-associated receptor (OSCAR) and tartrate-resistant acid phosphatase (TRAP) were determined to investigate the effects of HMGB-1 loss on osteoclastogenesis. RESULTS: Single HMGB-1 deletion exerted no significant effect on rat trabeculae, serum ALP and osteocalcin. Noticeably, HMGB1 knockdown dramatically ameliorated OVX-induced changes in above indexes. Trabeculae structures of OVX rats were sparse with disorder arrangement, which were greatly recovered after HMGB-1 deletion. Enhanced osteoclastogenesis was observed in OVX rats by increasing number of TRAP + cells and expression of TRAP and OSCAR, and loss of HMGB1 ameliorated osteoclastogenesis in OVA rats. Moreover, HMGB-1 deletion antagonized OVX-evoked downregulation of osteoblast activity markers osterix (OSX), collagen type I alpha 1(COL1A1) and distal-less homeobox 2 (DLX2) protein. Furthermore, loss of HMGB-1 attenuated fluctuation of inflammatory factors in OVX rats. Additionally, HMGB-1 deficiency inhibited OVX-evoked activation of the Toll-like receptor (TLR) 4/NF-κB signaling pathway. Moreover, reactivating the TLR4 signaling further aggravated OVX-induced osteoporosis, which was reversed by HMGB1 knockdown. CONCLUSION: HMGB-1 deletion alleviated OVX-triggered osteoporosis by suppressing osteoclastogenesis and inflammatory disorder via the inhibition of the TLR4 signaling. Therefore, HMGB-1 may be a promising therapeutic target for osteoporosis.

Metabolic syndrome, hypertension, and hyperglycemia were positively associated with knee osteoarthritis, while dyslipidemia showed no association with knee osteoarthritis.

OBJECTIVE: Metabolic syndrome (MetS) is a clustering of at least three of the following four medical conditions: obesity, hypertension, dyslipidemia, and hyperglycemia. We aimed to discover the relationships between these diseases and osteoarthritis (OA) of the knee. METHODS: We searched four databases (EMBASE, PubMed, Cochrane Library, and MEDLINE), as well as articles on websites and conference materials. Study effect estimates and their 95% confidence intervals (CIs) were extracted and calculated. Sensitivity analyses were undertaken to determine inter-study heterogeneity. Finally, we tested for publication bias to determine whether the outcome of the meta-analysis was robust. RESULTS: A total of 1609 articles were identified, 40 of which were included. In radiological studies, the relationships with OA were increased for people with the following diseases: metabolic syndrome (OR 1.418, 95% CI 1.162 to 1.730), hypertension (OR 1.701, 95% CI 1.411 to 2.052), and hyperglycemia (OR 1.225, 95% CI 1.054 to 1.424). In symptomatic studies, the outcomes were similar in metabolic syndrome (OR 1.174, 95% CI 1.034 to 1.332) and hypertension (OR 1.324, 95% CI 1.186 to 1.478) studies, while there were no associations in hyperglycemia (OR 0.975, 95% CI 0.860 to 1.106) studies. There was no correlation between dyslipidemia and OA, whether in radiological studies (OR 1.216, 95% CI 0.968 to 1.529) or symptomatic studies (OR 1.050, 95% CI 0.961 to 1.146). CONCLUSIONS: In both studies, metabolic syndrome and hypertension were positively associated with knee OA, and dyslipidemia showed no correlations. Hyperglycemia was associated with OA in radiological studies, while results were reversed in symptomatic studies. Key Points • The hypothesis that metabolic syndrome and its components increase the risk for knee osteoarthritis is attractive; thus, this meta-analysis may help us find out the answer. • There were lots of large-scale studies here, and the total participants were considerable; and this meta-analysis was relatively robust because of reasonable heterogeneity and publication bias. • Targeted education and effective management of risk factors may be helpful for reducing the prevalence of knee osteoarthritis.

Spinal intraosseous schwannoma without spinal canal and neuroforamina involvement: A case report.

BACKGROUND: Spinal intraosseous schwannomas (SIS) are rare, and as yet have not been fully described in the literature. The first case of SIS was reported in 1971, and 24 cases of SIS have been reported so far. However, including the present case, there are only seven cases without spinal canal and neuroforamina involvement. CASE SUMMARY: A 56-year-old man presented with a history of neck pain for 2 years. An obvious osteolytic destruction of the seventh cervical (C7) vertebra was observed on imaging examination. Magnetic resonance imaging of the cervical spine showed space-occupying lesions in the C7 vertebra, and destruction of the anterior cortex of the vertebra. The lesions had an exophytic component that extended from the C7 vertebra into the soft tissue on the front side. The foramen transversarium on both sides were intact. The patient underwent surgical biopsy and focal excision of the C7 lesion. The diagnosis of "schwannoma" was verified by postoperative pathological examinations. In a review of the literature, this is the seventh case of SIS without spinal canal and neuroforamina involvement, and the third reported case of type VIII SIS. We discussed our case with respect to reported classification characteristics of SIS. CONCLUSION: SIS is a very rare tumor. We report a rare case that may be important for further classification of osteo-schwannoma. The establishment of a complete disease classification is of high importance for the treatment and prognosis of this disease. Thus, more basic studies and retrospective analysis of related cases are necessary.

Alkaline-phosphatase triggered self-assemblies enhances the anti-inflammatory property of methylprednisolone in spinal cord injury.

Methylprednisolone sodium phosphate (MP) is an anti-inflammatory corticosteroid which is used in the treatment of spinal cord injury (SCI), however the overdose of MP has toxic effects Therefore it is prerequisite to develop novel approaches to overcome the side effects of MP and enhance its efficacy. In the present work, we have developed alkaline phosphatase (ALP) trigger self-assembly system of oligopeptides to physically entrap and locally deliver MP. The synthesis of Nap-Phe-Phe-Tyr(H2PO3)-OH (1P) was achieved using solid phase peptide synthesis and was characterized using mass spectroscopy. The 1P is a hydrogelator, which in presence of ALP self-assembles to form the hydrogel. During the self-assembly of 1P, MP was physically entrapped without losing the physical strength of hydrogel as revealed in the rheology study. The consistency of this hydrogel and the structure was characterized using circular dichroism. The MP was released from the hydrogel in a sustain manner and 80% of the drug release was observed at 120 h. The MP + 1P were non-toxic to the cells at lower concentration however toxicity increases with the increase in concentration of MP. Further, the in-vivo administration of MP + 1P significantly reduces the pro-inflammatory cytokines and the histological analysis revealed improvement in the SCI. In conclusion, it could be stated that the synthesis of 1P for the delivery of MP provides the novel opportunity in for the treatment of SCI.

LncRNA CASC11 is upregulated in postmenopausal osteoporosis and is correlated with TNF-α.

PURPOSE: In this study, we aimed to investigate the role of lncRNA cancer susceptibility 11 (CASC11) and tumor necrosis factor (TNF-α) in postmenopausal osteoporosis (POP). METHODS AND MATERIALS: POP patients and healthy controls were included in this study and levels of CASC11 and TNF-α in plasma of those participants were measured by qPCR and Western blot, respectively. ROC curve was used for diagnostic analysis. Patients were followed up for 2 years and the correlations between the levels of CASC11 and TNF-α and disease conditions were analyzed. RESULTS: We found that CASC11 and TNF-α were both upregulated in plasma of POP patients than in healthy controls. Plasma levels of CASC11 and TNF-α were positively correlated in both POP patients and in healthy controls. Upregulation of CASC11 and TNF-α distinguished POP patients from healthy controls. Treatment and follow-up study showed that high CASC11 levels were significantly correlated with prolonged treatment course and high recurrence rate. Plasma levels of CASC11 and TNF-α decreased after treatment. CASC11 overexpression led to upregulated TNF-α in osteoclasts. CONCLUSION: CASC11 is upregulated in POP and is correlated with TNF-α.

Docosahexaenoic acid inhibits bone remodeling and vessel formation in the osteochondral unit in a rat model.

OBJECTIVES: We aimed to determine whether bone remodeling and vessel formation in the osteochondral unit are suppressed by supplementing with docosahexaenoic acid in anterior cruciate ligament transection (ACLT)-induced rats. METHODS: Twelve-week-old male Sprague Dawley rats were randomized to sham-operated, ACLT-operated and treated with vehicle, or ACLT-operated and treated with DHA groups. Micro-architecture and vasculature in the tibial osteochondral unit were examined by micro-CT, as well as by histomorphometry. To evaluate the effects of DHA in vitro, we conducted functional and expressional assays in RAW264.7 cells and HUVECs. Finally, we used OARSI-modified Mankin criteria and histological analyses to assess the status of the cartilage layer. RESULTS: Microstructural parameters in the osteochondral unit showed that bone mass loss and angiogenesis were less in DHA-treated rats than in vehicle-treated rats. Immunofluorescence-positive cells labeled with TRAP, RANKL, CD31, and endomucin agents in the osteochondral unit of ACLT-operated rats were reduced in the DHA-treated group compared with the vehicle-treated group. Furthermore, the number of TRAP-stained cells, areas of bone resorption pits, and mRNA expression of TRAP, CTSK, MITF, and NFATC1 were reduced in RAW264.7 cells treated with RANKL + DHA compared with those treated with only RANKL. Tube formation, proliferation and migration of HUVECs, and VEGF-C mRNA and VEGFR2 protein expression were inhibited by DHA. The decrease in OARSI score, and MMP-13 and collagen X expression suggested that DHA attenuated cartilage degeneration. CONCLUSIONS: DHA has the ability to restrain bone remodeling and vessel formation in the osteochondral unit, which may contribute to protection of cartilage.

Therapeutic effects of new-type hydraulic delivery vertebroplasty, balloon kyphoplasty and conventional pusher-type vertebroplasty on single segmental osteoporotic vertebral compression fracture.

This study aims to evaluate safety and practicality in clinical application for better guidance of single segmental osteoporotic vertebral compression fractures treatment. From May 2012 to September 2013, a total of 188 cases of patients with fractures, who received different treatment, were incorporated in the study and then divided into: group A (n=59), conventional pusher-type vertebroplasty; group B (n=54), balloon kyphoplasty; group C (n=60), new-type hydraulic delivery vertebroplasty treatment. The overall follow-up rate was 92.02%. Postoperative visual analogue scale (VAS) and Oswestry disability index (ODI) scores were significantly improved more than those of the preoperative scores in the three groups. Bone cement injection volumes in group A were significantly lower than those in group B and group C. Vertebral height recovery rates among groups were obviously different, showing statistical significance. After a year of follow-up, the vertebral height recovery outcome in group A was obviously poorer than that in group B and group C. A poorer outcome in group B was also found when compared with group C. In addition, the vertebral height restoration had a certain degree of loss, with the loss rate of 20.5, 14.0 and 7.5% in the three groups, respectively. Three operation methods have equivalent effects in the improvement of symptoms and functional recovery. Therefore, the new-type hydraulic delivery vertebroplasty provides a relatively more concise operation and shorter operation time, displaying more outstanding performance of clinical efficacy in spinal reconstruction and reduction of complications risks by evaluating the diffusion of the bone cement, vertebral height restoration rate and postoperative complications.

The antipsychotic drug pimozide inhibits cell growth in prostate cancer through suppression of STAT3 activation.

Currently, drug discovery and development for clinical treatment of prostate cancer has received increased attention, specifically the STAT3 inhibitor. Our previous study reported that the neuroleptic drug pimozide had antitumor activity against hepatocellular carcinoma cells or stem-like cells through suppressing the STAT3 activity. In the present study we demonstrate that pimozide inhibits cell growth and cellular STAT3 activation in prostate cancer cells. Our results showed that pimozide inhibited prostate cancer cell proliferation in a dose- and time-dependent manner by inducing G1 phase cell cycle arrest, downregulated the ability of colony formation and sphere forming, as well as suppressed cells migration in both DU145 and LNCaP cells. Surprisingly, pimozide reduced the basal expression of phosphorylation STAT3 at tyrosine 705 and reversed the expression of phosphorylation of STAT3 induced by IL-6 addition, suggesting that pimozide can suppress cellular STAT3 activation. Thus, the antipsychotic agent pimozide may be a potential and novel therapeutic for patients with advanced prostate cancer.

Significance of increased leptin expression in osteoarthritis patients.

OBJECTIVE: Alterations in leptin expression contributes to the progression of various diseases, including cancers. This meta-analysis investigated the clinical significance of leptin levels in osteoarthritis (OA) patients, with the goal of building a leptin-based diagnostic criterion for OA. METHOD: Multiple scientific databases in English and Chinese languages, such as the Cochrane Library Database, CINAHL, Chinese Biomedical (CBM), EMBASE, PubMed, and Web of Science, were exhaustively searched, without any language restrictions, to identify high-quality studies relevant to leptin and OA. Version 12.0 STATA software was used for data analysis. We used odds ratios (OR) and 95% confidence intervals (CI) to test the correlation between serum leptin levels and OA progression. RESULTS: A total of 11 clinical studies were finally selected for their high quality and relevance to the topic in this meta-analysis. The 11 case-control studies contained a combined total of 3,625 subjects. The meta-analysis results showed that leptin expression was significantly increased in OA patients, compared with the controls (SMD = 0.87, 95%CI: 0.72-1.02, P < 0.001), and there was also a strong association between leptin expression levels and gender (SMD = 8.55, 95%CI: 4.74-12.35, P < 0.001). In ethnicity-stratified subgroup analysis, all the study populations, irrespective of ethnicity, showed remarkably high leptin expression levels in females and in OA patients (all P < 0.05), compared to their respective counterparts. CONCLUSION: The present study revealed that increased leptin expression levels are associated with disease severity in OA patients, especially among the female OA patients. Based on our results, we propose that leptin level may be a useful biomarker for the assessment of the clinical status in OA patients.