Ting Qiu

Animal models for glucocorticoid-induced postmenopausal osteoporosis: An updated review

Glucocorticoid-induced postmenopausal osteoporosis is a severe osteoporosis, with high risk of major osteoporotic fractures. This severe osteoporosis urges more extensive and deeper basic study, in which suitable animal models are indispensable. However, no relevant review is available introducing this model systematically. Based on the recent studies on GI-PMOP, this brief review introduces the GI-PMOP animal model in terms of its establishment, evaluation of bone mass and discuss its molecular mechanism. Rat, rabbit and sheep with their respective merits were chosen. Both direct and indirect evaluation of bone mass help to understand the bone metabolism under different intervention. The crucial signaling pathways, miRNAs, osteogenic- or adipogenic- related factors and estrogen level may be the predominant contributors to the development of glucocorticoid-induced postmenopausal osteoporosis.

Risk factors for recollapse of the augmented vertebrae after percutaneous vertebroplasty for osteoporotic vertebral fractures with intravertebral vacuum cleft.

Abstract To determine risk factors related to recollapse of the augmented vertebrae after percutaneous vertebroplasty (PVP) for osteoporotic vertebral compression fractures (OVCFs) with intravertebral vacuum cleft (IVC). Fifty-two patients treated with PVP for single OVCFs with the IVC were retrospectively reviewed. The follow-up period was at least 2 years. Vertebral height loss ≥15% or kyphotic angle ≥10° at the final follow-up in relation to the immediately postoperative values were adopted as a definition of recollapse of the augmented vertebrae. Correlation analysis and multiple logistic regression analyses were performed to elucidate the related clinical or radiological factors for recollapse of the augmented vertebrae including age, gender, bone mineral density, preoperative fracture severity, locations of IVC sign, distribution patterns of polymethylmethacrylate (PMMA), reduction rate, and reduction angle. Assuming the increase of height loss more than 15% as a criterion of recollapse, only cleft filling pattern of PMMA in the IVC area was a significant risk factor for recollapse of the augmented vertebrae (P < 0.01). Assuming ≥10° progression of kyphotic angle as a criterion, cleft filling pattern of PMMA and higher values of reduction angle was as 2 significant risk factors for recollapse of the augmented vertebrae (P < 0.01). No significant difference was found in other clinical and radiological factors (P > 0.05). Cleft filling pattern of PMMA and higher values of reduction angle may play an important role in inducing recollapse of the augmented vertebrae after PVP for OVCFs with the IVC. Careful observation of patients with these conditions is necessary to prevent deterioration of their clinical course.

Implications of the Interaction Between miRNAs and Autophagy in Osteoporosis

Abstract Imbalances between bone formation and resorption are the primary cause of osteoporosis. However, currently, a detailed molecular mechanism of osteoporosis is not available. Autophagy is the conserved process characterized by degrading and recycling aggregated proteins, intracellular pathogens, and damaged organelles. MicroRNAs (miRNAs) are novel regulatory factors that play important roles in numerous cellular processes, including autophagy, through the posttranscriptional regulation of gene expression. Conversely, autophagy plays a role in the regulation of miRNA homeostasis. Recent advances have revealed that both autophagy and miRNAs are involved in the maintenance of bone homoeostasis, whereas the role of the interaction of miRNAs with autophagy in osteoporosis remains unclear. In this paper, we review previous reports on autophagy, miRNAs, and their interaction in osteoporosis.

Mammalian Target of Rapamycin As a Therapeutic Target in Osteoporosis.

The mechanistic target of rapamycin (mTOR) plays a key role in sensing and integrating large amounts of environmental cues to regulate organismal growth, homeostasis, and many major cellular processes. Recently, mounting evidences highlight its roles in regulating bone homeostasis, which sheds light on the pathogenesis of osteoporosis. The activation/inhibition of mTOR signaling is reported to positively/negatively regulate bone marrow mesenchymal stem cells (BMSCs)/osteoblasts‐mediated bone formation, adipogenic differentiation, osteocytes homeostasis, and osteoclasts‐mediated bone resorption, which result in the changes of bone homeostasis, thereby resulting in or protect against osteoporosis. Given the likely importance of mTOR signaling in the pathogenesis of osteoporosis, here we discuss the detailed mechanisms in mTOR machinery and its association with osteoporosis therapy.

Promotion effect of extracts from plastrum testudinis on alendronate against glucocorticoid-induced osteoporosis in rat spine

Alendronate (ALN) is a key therapeutic used to treat glucocorticoid-induced osteoporosis (GIOP), but may induce severe side effects. We showed earlier that plastrum testudinis extracts (PTE) prevented and treated GIOP in vivo. However, clinically, PTE is seldom used alone. Herein, we reveal the synergistic effect of ALN and PTE can treat GIOP of the rat spine and define the mechanism. Sprague-Dawley rats were randomly assigned to four groups: a vehicle group, a GIOP group, an ALN group, and an ALN+PTE group. Each group was further divided into two experimental phases, including dexamethasone (DXM) intervention and withdrawal. Bone mass, microarchitecture, biomechanics, bone-turnover markers, and histomorphology were evaluated. The mRNA and protein expression levels of CTSK and Runx2 were detemined. We found that ALN+PTE improved bone quantity and quality, bone strength, bone turnover; and mitigated histological damage during glucocorticoid intervention and withdrawal. The therapeutic effect was better than that afforded by ALN alone. ALN+PTE reduced CTSK protein expression, promoted Runx2 mRNA and protein expression to varying extents, and more strongly inhibited bone resorption than did ALN alone. Overall, the synergistic effect mediated by ALN+PTE reversed GIOP during DXM intervention and withdrawal via affecting CTSK and Runx2 expression at mRNA and protein levels.

Efficacy and safety of the target puncture technique for treatment of osteoporotic vertebral compression fractures with intravertebral clefts

Objective To compare the efficacy and safety of our target puncture technique with the traditional technique during percutaneous kyphoplasty (PKP) for osteoporotic vertebral compression fractures (OVCFs) with intravertebral clefts (IVCs). Methods 104 patients treated with PKP for single OVCFs with IVCs were retrospectively reviewed. All patients were divided into three groups: cleft filling by the traditional technique (Group A, n=18); interdigitated filling (Group B, n=50); and overfilling by the target technique (Group C, n=36). Oswestry disability index (ODI) and visual analog scale (VAS) scores and radiological evidence of vertebral body height and kyphotic angle, cement leakage, and adjacent vertebral fractures were studied before and after surgery (immediate, 1 and 2 years). Results The ODI and VAS scores decreased for all patients and no significant difference was found between the three groups after treatment. However, 1 and 2 years after surgery a greater increase in ODI and VAS scores was observed in Group A compared with the other two groups. The initial correction of vertebral body height and kyphotic angle was not significant among the three groups. However, loss of correction was greater in Group A. No significant difference was found in cement leakage. The incidence of adjacent vertebral fractures in Group C was higher than in the other two groups. Conclusions Different puncture techniques were initially effective for all patients with IVCs. However, cement cleft filling by the traditional technique was found to have less stability causing higher VAS/ODI scores and greater loss of correction. Hence, our target puncture technique was recommended in this study.

Extracts from plastrum testudinis reverse glucocorticoid-induced spinal osteoporosis of rats via targeting osteoblastic and osteoclastic markers

Extracts from plastrum testudinis (PTE), an important traditional Chinese medicine, have been demonstrated promotion of osteoblastic function in vitro. This study aims to investigate the protective effect of PTE on glucocorticoid-induced osteoporosis(GIOP) in vivo and analyze therapeutic targets of PTE on GIOP. SD rats were randomly assigned to two experiments: preventive and therapeutic experiments, in which rats respectively received oral PTE at the same time of glucocorticoid injection or after glucocorticoid injection inducing osteoporosis. BMD, microarchitecture, biomechanics, bone metabolism markers and histomorphology were evaluated. mRNA and protein expression of OPG, Runx2, CTSK and MMP9 were examined.Results showed bone quality and bone quantity were significantly elevated by PTE. Histomorphometry showed thicker and denser bone trabecularsand more osteoblasts and less osteoclasts in group of PTE intervention. The mRNA expression of OPG was significantly upregulated whereas expression of CTSK was significantly downregulatedin different groups of PTE intervention. Stronger immunostaining for Runx2 and weaker immunostaining for CTSK were observed in groups of PTE intervention. This demonstrated that PTE may reverse GIOP in prevention and management via targeting OPG, Runx2 and CTSK in mRNA and protein levels.

Therapeutic potential of microRNAs in osteoporosis function by regulating the biology of cells related to bone homeostasis: ZHAO et al.

MicroRNAs (miRNAs) are novel regulatory factors that play important roles in numerous cellular processes through the posttranscriptional regulation of gene expression. Recently, deregulation of the miRNA‐mediated mechanism has emerged as an important pathological factor in osteoporosis. However, a detailed molecular mechanism between miRNAs and osteoporosis is still not available. In this review, the roles of miRNAs in the regulation of cells related to bone homeostasis as well as miRNAs that deregulate in human or animal are discussed. Moreover, the miRNAs that act as clusters in the biology of cells in the bone microenvironment and the difference of some important miRNAs for bone homeostasis between bone and other organs are mentioned. Overall, miRNAs that contribute to the pathogenesis of osteoporosis and their therapeutic potential are considered.

Autophagy as a target for glucocorticoid-induced osteoporosis therapy

Autophagy takes part in regulating the eukaryotic cells function and the progression of numerous diseases, but its clinical utility has not been fully developed yet. Recently, mounting evidences highlight an important correlation between autophagy and bone homeostasis, mediated by osteoclasts, osteocytes, bone marrow mesenchymal stem cells, and osteoblasts, and autophagy plays a vital role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP). The combinations of autophagy activators/inhibitors with anti-GIOP first-line drugs or some new autophagy-based manipulators, such as regulation of B cell lymphoma 2 family proteins and caspase-dependent clearance of autophagy-related gene proteins, are likely to be the promising approaches for GIOP clinical treatments. In view of the important role of autophagy in the pathogenesis of GIOP, here we review the potential mechanisms about the impacts of autophagy in GIOP and its association with GIOP therapy.

Plastrum Testudinis Extracts Promote BMSC Proliferation and Osteogenic Differentiation by Regulating Let-7f-5p and the TNFR2/PI3K/AKT Signaling Pathway

Background/Aims: Plastrum testudinis extracts (PTE) show osteoprotective effects on glucocorticoid-induced osteoporosis in vivo and in vitro. However, the underlying molecular mechanism of PTE in promoting osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is unclear. Methods: BMSC proliferation was investigated using the Cell Counting Kit-8 assay. BMSC differentiation and osteogenic mineralization were assayed using alkaline phosphatase and Alizarin red staining, respectively. The mRNA expression levels of Let-7f-5p, Tnfr2, Traf2, Pi3k, Akt, β-catenin, Gsk3β, Runx2, and Ocn were measured using real time quantitative polymerase chain reaction. Protein levels of TNFR2, TRAF2, p-PI3K, p-AKT, p-β-CATENIN, and p-GSK3β were analyzed by western blotting. The functional relationship of Let-7f-5p and Tnfr2 was determined by luciferase reporter assays. Results: The optimum concentration for PTE was 30 μg/ml. PTE significantly promoted BMSC osteogenic differentiation and mineralization after 7 and 14 days in culture, respectively. The combination of PTE and osteogenic induction exhibited significant synergy. PTE upregulated Let-7f-5p, β-catenin, Runx2, and Ocn mRNA expression, and downregulated Tnfr2, Traf2, Pi3k, Akt, and Gsk3β mRNA expression. PTE inhibited TNFR2, TRAF2, and p-β-CATENIN protein expression, and promoted p-PI3K, p-AKT, and p-GSK3β protein expression. In addition, Tnfr2 was a functional target of Let-7f-5p in 293T cells. Conclusions: Our results suggested that PTE may promote BMSC proliferation and osteogenic differentiation via a mechanism associated with the regulation of Let-7f-5p and the TNFR2/PI3K/AKT signaling pathway.