Icariin is the major active ingredient in Herba epimedii which is a commonly used Chinese herbal medicine for the treatment of osteoporosis. The present study aims to evaluate the osteoprotective effect of Icariin in glucocorticoid-induced osteoporosis in vivo and investigate the effect of Icariin on glucocorticoid-induced osteocyte apoptosis in vitro. A total of 48 female Sprague-Dawley rats were used. Glucocorticoid-induced osteoporosis was induced by daily injections of dexamethasone (0.1 mg/kg, daily, s.c.) for 60 days, whereas sham animals were injected daily with vehicle. At the end of the osteoporosis development period, osteoporotic rats were randomized to receive: vehicle (n = 8), Icariin (5,125 mg/kg, i.g.; n = 8), or alendronate (0.03 mg/kg, s.c.; n = 8) for 12 weeks. Sham animals were treated with vehicle for 12 weeks. At the beginning and at the end of treatments, animals were examined for bone mineral density. Serum bone-alkaline phosphatase and carboxy-terminal collagen cross links were measured. Primary osteocytes were isolated, and apoptosis was determined by trypan-blue assay. Interaction between Icariin and estrogen receptor and prosurvival signaling pathways activated by Icariin were also investigated. Icariin showed a comparable efficacy with alendronate in increasing bone mass. Icariin significantly increased bone-alkaline phosphatase (bone formation marker) and reduced carboxy-terminal collagen cross links (bone resorption marker). In vitro studies demonstrated that Icariin significantly prevented GC-induced apoptosis in osteocytes by activating ERK signaling via estrogen receptor. Our results suggest that Icariin might exert osteoprotective effect by maintaining osteocyte viability, thereby, regulating bone remodeling. Furthermore, our study provides preclinical evidence for the efficacy of Icariin for management of Glucocorticoid-induced osteoporosis.

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Circular RNAs (circRNAs) are a novel class of noncoding RNAs that are widely expressed in human disease. However, circRNAs expression profile and potential mechanism in osteoporosis pathogenesis remain to be further studied. In the present study, a total of 69 circRNAs were identified to be abnormally expressed in osteoporosis patient samples by microarray and bioinformatics analyses. We found that circ_0011269 was notably downregulated in osteoporosis (fold change, 3.94). By means of miRanda algorithm, we constructed the interaction network of circ_0011269-miRNAs in osteoporosis based on target binding and miR-122 was enrolled in the network. Dual-luciferase reporter assay verified the target relationship of miR-122 and circ_0011269/RUNX2. The expression of circ_0011269 and RUNX2 were gradually increased during osteogenic differentiation while miR-122 exhibited a decreased expression. Moreover, overexpression of circ_0011269 could promote RUNX2 expression and inhibit osteoporosis. In summary, this study found that circ_0011269 sponges miR-122 to regulate RUNX2 expression and promotes osteoporosis progression.

BackgroundFew studies have examined the efficacy of recombinant human bone morphogenetic protein-2 (rhBMP-2) in 2-level anterior cervical discectomy and fusion (ACDF). The purpose of this study was to compare the outcomes in a series of patients with CSM treated with 2-level ACDF with or without rhBMP-2.Material/MethodsThe retrospective study included a total of 146 patients with CSM. The rhBMP-2 group consisted of 73 patients who underwent 2-level ACDF with rhBMP-2. A total of 73 patients who also received 2-level ACDF with autogenous ICBG alone were included in the matched-pair ICBG group with a ratio of 1:1, based on age, sex, and BMI. All data, including fusion rate and time, VAS, JOA score, operative date, and complications, were assessed.ResultsWith respect to the length of hospital stay, operative times, and blood loss, there were no significant difference between the 2 groups. However, the rhBMP-2 group presented a shorter fusion time (P<0.013) and higher fusion rate (P<0.036) than the ICBG group. In the rhBMP-2 group, 22% required additional treatment for complications compared to 18% of patients in the ICBG group, which showed no significant difference (P=0.543).ConclusionsThe application of rhBMP-2 in 2-level ACDF showed higher fusion rates, shorter fusion time, and similar function outcomes compared to those who received ACDF with ICBG alone.

Objective: Chondrosarcoma is the second most common primary bone sarcoma; however, unlike other tumors, the biopsy cannot easily make a definite diagnosis or predict the histological grade. This meta-analysis was performed to evaluate the utility of 18 F-FDG PET and PET/CT to differentiate chondrosarcoma from benign cartilaginous lesions and to predict the histopathological grade of chondrosarcoma. Material and methods: A comprehensive search was performed in three electronic databases including Medline/ PubMed, the Cochrane Library and Embase to retrieve diagnostic studies evaluating the role of 18 F-FDG PET or PET/ CT for appraising the status of chondrosarcoma. Reference lists of related articles were also scrutinized manually. Useful data were extracted to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), the summary receiver operating characteristic curve (sROC), and the area under the curve (AUC) of 18 F-FDG PET or PET/CT in diagnosing chondrosarcoma, and pooled weighted mean differences (WMD) of maximum standardized uptake value (SUVmax) between different entities of cartilaginous neoplasms by using Stata 19.0. Results: A total of twelve studies provided sufficient data for the quantitative analysis. For the diagnosis of chondrosarcoma, the pooled sensitivity, specificity, and DOR of 18 F-FDG PET were 0.84 (95% confidence interval [CI] 0.46 to 0.97), 0.82 (95% CI 0.55 to 0.94), and 24.244 (95% CI 1.985 to 96.148), respectively while those of 18 F-FDG PET/CT were 0.94 (95% CI 0.86 to 0.97), 0.89 (95% CI 0.82 to 0.93), and 112.999 (95% CI 41.341 to 308.866), respectively. The pooled WMD of SUVmax were − 0.89 (95% CI −1.67 to −0.10) between benign cartilaginous lesions and grade 1 (G1) chondrosarcoma, −1.94 (95% CI −2.76 to −1.12) between G1 and grade 2 (G2) chondrosarcoma, and − 2.37 (95% CI −5.79 to 1.05) between G2 and grade 3 (G3) chondrosarcoma. Conclusions: In a word, 18 F-FDG PET/CT revealed excellent accuracy in the diagnosis of chondrosarcoma and might assist in clinical decision-making. Meanwhile, although SUVmax alone showed restricted ability to differentiate benign cartilaginous lesions and G1 chondrosarcoma, as well as between G2 and G3 chondrosarcoma, it can identify intermediate/high-grade chondrosarcoma from low-grade ones.

Heterotopic ossification (HO) is characterized by extraskeletal ossification in soft tissue. Thus far, there is a lack of effective drug therapy against HO. Loss of PTEN in osteoblasts has been reported to accumulate bone mass in skeletal development and promote fracture healing in association with the activation of the PI3K/AKT pathway. However, the role of the PTEN/PI3K/AKT signaling in HO pathogenesis remains unknown. The present study investigated the implication of this pathway during BMP2-induced osteogenic differentiation and ectopic bone formation. It was shown that overexpression of PTEN inhibited proliferation but stimulated apoptosis in mesenchymal pluripotent C3H10T1/2 cells. PTEN also inhibited BMP2-induced osteoblast differentiation, whereas BMP2 repressed PTEN expression and subsequently activated PI3K/AKT. The PI3K inhibitor, LY294002, blocked BMP2-induced osteoblastogenesis, suggesting that the PI3K/AKT pathway is critically required for BMP2 to initiate osteoblastogenesis. In vivo , implantation of BMP2 in muscle induced ectopic endochondral ossification. Strikingly, this bone-forming capacity was notably suppressed by the PI3K inhibitor LY294002. Hence, the results of the present study demonstrated that the PI3K/AKT signaling activity is indispensable for BMP2 to induce ectopic new bone. Targeting the PI3K/AKT pathway using inhibitor(s) may represent a potential molecular therapy for the treatment against HO.

Human osteoclast-stimulating factor (hOSF) is an intracellular protein produced by osteoclasts that induces osteoclast formation and bone resorption. The protein contains a modular Src homology 3 (SH3) domain that mediates the intermolecular recognition and interaction of hOSF with its biological partners. Here, we proposed targeting the hOSF SH3 domain to disrupt hOSF-partner interactions for bone disease therapy by using SH3 inhibitors. In the procedure, the primary sequences of three known hOSF-interacting proteins (c-Src, SMN and Sam68) were parsed, from which totally 31 octapeptide segments that contain the core SH3-binding motif PXXP were extracted, and their binding behavior to hOSF SH3 domain was investigated at structural level using a biomolecular modeling protocol. Several SH3-binding candidates were identified theoretically and then determined to have high or moderate affinity for the domain using fluorescence spectroscopy assays. One potent peptide (425) APPARPVK(432) (Kd  = 3.2 μM), which corresponds to the residues 425-432 of Sam68 protein, was used as template to derive N substitution of peptides (peptoids). Considering that proline is the only endogenous N-substituted amino acid that plays a critical role in SH3-peptide binding, the substitution was addressed at the two key proline residues (Pro427 and Pro430) of the template peptide with nine N-substituted amino acid types. By systematically evaluating the structural and energetic effects of different N-substituted amino acids presenting at the two proline sites on peptide binding, we rationally designed five peptoid inhibitors and then determined in vitro their binding affinity to hOSF SH3 domain. Consequently, two designed peptoids APPAR(N-Clp)VK and APPAR(N-Ffa)VK with Pro430 replaced by N-Clp and N-Ffa were confirmed to have increased (Kd  = 0.87 μM) and comparable (Kd  = 2.9 μM) affinities relative to the template, respectively. In addition, we also found that the Pro427 residue plays an essential role in restricting peptide/peptoid conformations to polyproline II (PPII) helix as the basic requirement of SH3 binding so that the residue cannot be modified. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

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