Mechanical strain regulates osteogenesis via Antxr1/LncRNA H19/Wnt/ß-catenin axis.

Alleviating bone loss is an essential way to prevent osteoporotic fractures. Proper exercise improves bone density without the side effects of long-term medications, but the mechanism is unclear. Our study explored the role of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of exercise-mediated alleviation of bone loss. Here we discovered that moderate-intensity treadmill exercise alleviates bone loss caused by ovariectomy and ameliorates bone strength accompanied by an increased lncRNA H19 expression. Concomitantly, Antxr1, a mechanosensitive protein was found downregulated by exercise but upregulated by ovariectomy. Interestingly, knockdown expression of Antxr1 increased lncRNA H19 expression and Wnt/ß-catenin signaling pathway in bone marrow mesenchymal stem cells, whereas overexpression of Antxr1 decreased lncRNA H19 expression and Wnt/ß-catenin signaling pathway. Hence, our study demonstrates the regulation of Antxr1/LncRNA H19/Wnt/ß-catenin axis in the process of mechanical strain-induced osteogenic differentiation, which provides further mechanistic insight into the role of mechanical regulation in bone metabolism.

Exercise improved bone health in aging mice: a role of SIRT1 in regulating autophagy and osteogenic differentiation of BMSCs.

Introduction: This study was designed to investigate the effect of running exercise on improving bone health in aging mice and explore the role of the SIRT1 in regulating autophagy and osteogenic differentiation of Bone marrow Mesenchymal Stem Cells (BMSCs). Methods: Twelve-month-old male C57BL/6J mice were used in this study as the aging model and were assigned to treadmill running exercise for eight weeks. Non-exercise male C57BL/6J mice of the same old were used as aging control and five-month-old mice were used as young controls. BMSCs were isolated from mice and subjected to mechanical stretching stimulation in vitro. Results: The results showed that aging mice had lower bone mass, bone mineral density (BMD), and autophagy than young mice, while running exercise improved BMD and bone mass as well as upregulated autophagy in bone cells. Mechanical loading increased osteogenic differentiation and autophagy in BMSCs, and knockdown of SIRT1 in BMSCs demonstrated that SIRT1-regulated autophagy involved the mechanical loading activation of osteogenic differentiation. Conclusion: Taken together, this study revealed that exercise improved bone health during aging by activating bone formation, which can be attributed to osteogenic differentiation of BMSCs through the activation of SIRT1-mediated autophagy. The mechanisms underlying this effect may involve mechanical loading.

Novel application of HS-GC-IMS for characteristic fingerprints and flavor compound variations in citrus reticulatae pericarpium during storage with different Aspergillus niger fermentation.

Citrus reticulatae pericarpium (CRP) is regarded as a valuable functional food in many countries due to its pharmacological activities and unique aroma. In this study, CRP was treated by different A. niger to accelerate aging. Headspace-gas chromatography-ion mobility spectrometry (HS-GC-IMS) fingerprinting was adopted to rapidly and comprehensively evaluate the flavor compounds of CRP and to identify their dynamic changes at different storage time. Results revealed that the hesperidin content of DOL groups reduced more clearly than other groups during storage. A total of 134 volatile flavor compounds were identified. The volatile organic compounds (VOCs) showed that the lemon, sweet with the musk aroma of CRP, changed to apple, pineapple, and coffee odors during storage. The principal component analysis (PCA) and fingerprint similarity analysis (FSA) results showed that the CRP was clearly distinguished at different storage time. DOL-3 and DOS-6 differ the most from the DOW-3,6, respectively. This work provided helpful information for accelerating the aging of CRP and has great potential for industrial application.

Recent Developments in Molecular Characterization, Bioactivity, and Application of Arabinoxylans from Different Sources.

Arabinoxylan (AX) is a polysaccharide composed of arabinose, xylose, and a small number of other carbohydrates. AX comes from a wide range of sources, and its physicochemical properties and physiological functions are closely related to its molecular characterization, such as branched chains, relative molecular masses, and substituents. In addition, AX also has antioxidant, hypoglycemic, antitumor, and proliferative abilities for intestinal probiotic flora, among other biological activities. AXs of various origins have different molecular characterizations in terms of molecular weight, degree of branching, and structure, with varying structures leading to diverse effects of the biological activity of AX. Therefore, this report describes the physical properties, biological activities, and applications of AX in diverse plants, aiming to provide a theoretical basis for future research on AX as well as provide more options for crop breeding.

Role of Sostdc1 in skeletal biology and cancer.

Sclerostin domain-containing protein-1 (Sostdc1) is a member of the sclerostin family and encodes a secreted 28-32 kDa protein with a cystine knot-like domain and two N-linked glycosylation sites. Sostdc1 functions as an antagonist to bone morphogenetic protein (BMP), mediating BMP signaling. It also interacts with LRP6, mediating LRP6 and Wnt signaling, thus regulating cellular proliferation, differentiation, and programmed cell death. Sostdc1 plays various roles in the skin, intestines, brain, lungs, kidneys, and vasculature. Deletion of Sostdc1 gene in mice resulted in supernumerary teeth and improved the loss of renal function in Alport syndrome. In the skeletal system, Sostdc1 is essential for bone metabolism, bone density maintenance, and fracture healing. Recently, Sostdc1 has been found to be closely related to the development and progression of multiple cancer types, including breast, renal, gastric, and thyroid cancers. This article summarises the role of Sostdc1 in skeletal biology and related cancers to provide a theoretical basis for the treatment of related diseases.

Effects of exercise on the expression of long non-coding RNAs in the bone of mice with osteoporosis.

Physical activity or exercise are known to promote bone formation and decrease bone resorption to maintain skeletal and bone health both in animal models and in humans with osteoporosis. Previous studies have indicated that long non-coding RNAs (lncRNAs) are able to regulate bone metabolism. Therefore, the present study aimed to evaluate whether lncRNAs responded to exercise by regulating the balance of bone metabolism in order to prevent osteoporosis. To meet this end, ovariectomized mice were used in the present study to establish an osteoporosis model. The exercise treatment groups were subjected to 9 weeks of treadmill running exercise in 4 weeks of the operation was performed Femurs were collected to measure bone mineral density, bone mass, bone formation and resorption. The expression levels of lncRNAs were subsequently measured using microarray and gene function analyses. The pairwise comparison results [ovariectomy (OVX) vs. OVX + exercise (EX); OVX vs. SHAM; SHAM vs. SHAM + EX; OVX + EX vs. SHAM + EX] of the gene microarray analysis revealed that the expression of 2,424 lncRNAs (1718 upregulated and 706 downregulated) were significantly altered in the mouse femurs following treadmill running. Gene Ontology (GO) analysis, incorporating the GO annotations 'biological processes', 'molecular function' and 'cellular components', of osteoporosis revealed that the VEGF, mTOR and NF-κB signaling pathways were potential targets of the lncRNAs. Moreover, it was possible to predict the target microRNAs (miRNAs) of six lncRNAs (LOC105246953, LOC102637959, NONMMUT014677, NONMMUT027251, ri|D130079K21|PX00187K16|1491 and NONMMUT006626), which suggested that the underlying mechanism by which lncRNAs respond to exercise involved bone regulation via lncRNA-miRNA sponge adsorption. Overall, these results suggested that the treadmill running exercise did regulate lncRNA expression in the bone, and that this was involved in the prevention of osteoporosis.

The Role of Irisin in Exercise-Mediated Bone Health.

Exercise training promotes physical and bone health, and is the first choice of non-drug strategies that help to improve the prognosis and complications of many chronic diseases. Irisin is a newly discovered peptide hormone that modulates energy metabolism and skeletal muscle mass. Here, we discuss the role of irisin in bone metabolism via exercise-induced mechanical forces regulation. In addition, the role of irisin in pathological bone loss and other chronic diseases is also reviewed. Notably, irisin appears to be a key determinant of bone mineral status and thus may serve as a novel biomarker for bone metabolism. Interestingly, the secretion of irisin appears to be mediated by different forms of exercise and pathological conditions such as diabetes, obesity, and inflammation. Understanding the mechanism by which irisin is regulated and how it regulates skeletal metabolism via osteoclast and osteoblast activities will be an important step toward applying new knowledge of irisin to the treatment and prevention of bone diseases such as osteolysis and other chronic disorders.

MiR-214 Attenuates the Osteogenic Effects of Mechanical Loading on Osteoblasts.

Exercise is an effective way to prevent osteoporosis, but its mechanism remains unclear. MicroRNAs (miRNAs) play an essential role in bone metabolism. Recently, mechanical loading was reported to induce changes in miRNA expression in osteoblasts. However, the role of miRNAs in bone under exercise and its underlining mechanisms of action still remain unknown. MiR-214 was reported to regulate the process of osteogenesis and is considered a biomarker of osteoporosis. In this study, we aimed to investigate whether exercise could induce changes in miRNA expression in bone and to study the effects of miR-214 on mechanical loading-induced osteogenesis in osteoblasts. The results showed that miR-214 was down-regulated in both tibia from C57BL/6 mice after exercise in vivo and in osteoblasts after mechanical strain in vitro. Mechanical strain could enhance the ALP activity, promote matrix mineralization, up-regulate the expression of osteogenic factors such as ATF4, Osterix, ALP and ß-catenin, and down-regulate RANKL and RANK expression. Over-expression of miR-214 not only inhibited the expression of these osteogenic factors but also attenuated mechanical strain-enhanced osteogenesis in osteoblasts. Collectively, our results indicated that miR-214 could attenuate the osteogenic effects of mechanical loading on osteoblasts, suggesting that inhibition of miR-214 may be one of the ways in which exercise prevents osteoporosis.

The Effect of Exercise on the Prevention of Osteoporosis and Bone Angiogenesis.

Physical activity or appropriate exercise prevents the development of osteoporosis. However, the exact mechanism remains unclear although it is well accepted that exercise or mechanical loading regulates the hormones, cytokines, signaling pathways, and noncoding RNAs in bone. Accumulating evidence has shown that bone is a highly vascularized tissue, and dysregulation of vasculature is associated with many bone diseases such as osteoporosis or osteoarthritis. In addition, exercise or mechanical loading regulates bone vascularization in bone microenvironment via the modulation of angiogenic mediators, which play a crucial role in maintaining skeletal health. This review discusses the effects of exercise and its underlying mechanisms for osteoporosis prevention, as well as an angiogenic and osteogenic coupling in response to exercise.

Cyclic compression stimulates osteoblast differentiation via activation of the Wnt/ß-catenin signaling pathway.

It is widely accepted that mechanical stress is an important factor in bone associated cell differentiation, including that of mesenchymal stem cells, osteoblasts and osteocytes. The present study aimed to determine the effect of mechanical cyclic compressive load on osteoblast differentiation, and whether this was associated with activation of the wingless­type (Wnt)/ß-catenin signaling pathway. Using a 3D scaffold model, MC3T3­E1 cells were exposed to cyclic compressive loading via the Flexcell­5000C™ Compression system. Sinusoidal wave magnitudes of 0.33, 0.5 and 1 MPa were applied for 4, 6 and 8 h, at 1 Hz frequency. Expression levels of genes associated with osteoblast differentiation were enhanced following compression, including alkaline phosphatase, osteocalcin, runt­related transcription factor 2 and osterix. Optimal compression was observed using a magnitude of 0.5 MPa for 6 h, whereas a magnitude of 1 MPa had no effect on osteoblast differentiation, and had a negative effect when applied for prolonged time periods. Compressive loading additionally enhanced the mRNA expression levels of the Wnt/ß­catenin signaling pathway component, low density lipoprotein receptor­related protein 5, and the protein expression levels of Wnt1, disheveled segment polarity protein­2 (DVL2) and ß-catenin. By contrast, mRNA expression levels of sclerostin and the inactive form of ß-catenin (phosphorylated at Ser33/37/Thr41) were reduced following compressive loading. Following compressive loading of cells, dickkopf-related protein 1 (DKK­1), an inhibitor of the Wnt signaling pathway, increased protein expression levels of the inactive form of the Wnt­associated protein, phosphorylated­ß­catenin, compared with compression alone. However, DVL2 and Wnt1 protein expression levels were unaffected, suggesting that the loading­induced activation of Wnt/ß­catenin signaling decreased however, it was not prevented by DKK­1 treatment. In conclusion, the present study demonstrated that cyclic compressive load promoted osteoblast differentiation and may be dependent on the Wnt/ß-catenin signaling pathway in regard to magnitude and duration.

Mechanical Stress Regulates Bone Metabolism Through MicroRNAs.

There are many lines of evidence indicating that mechanical stress regulates bone metabolism and promotes bone growth. BMP, Wnt, ERK1/2, and OPG/RANKL are the main molecules thought to regulate the effects of mechanical loading on bone formation. Recently, microRNAs were found to be involved in bone cell proliferation and differentiation, regulating the balance of bone formation and bone resorption. Emerging evidence indicates that microRNAs also participate in mechanical stress-mediated bone metabolism, and is associated with disuse induced osteoporosis or osteopenia. Mechanical stress is able to induce expression of microRNAs that modulate the expression of osteogenic and bone resorption factors, leading to the positive impact of mechanical stress on bone. This review discusses the emerging evidence implicating an important role for microRNAs in the mechanical stress response in bone cells, as well as the challenges of translating microRNA research into potential treatment. J. Cell. Physiol. 232: 1239-1245, 2017. © 2016 Wiley Periodicals, Inc.