Osteoporosis: now and the future

Rachner, Tilman D.; Khosla, Sundeep; Hofbauer, Lorenz C.

doi:10.1016/s0140-6736(10)62349-5

Cited by 2,094 publications

(1,612 citation statements)

References 94 publications

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“…Two important regulating factors, receptor activator of nuclear factor κB ligand (RANKL) and macrophage‐colony stimulating factor (M‐CSF) are necessary for OC differentiation and survival 2. Dysregulation of osteoclastogenesis can lead to various bone disorders and the most common one is osteoporosis 3, 4. According to the International Osteoporosis Foundation, more than 200 million people suffer from this disease worldwide 5.…”

Section: Introductionmentioning

confidence: 99%

“…Nevertheless, the current first line antiresorptive drug bisphosphonate only solves the first problem which is increased osteoclastogenesis but left the second problem behind. The reason is that bisphosphonate inhibits both preosteoclast (POC) and mature OC without selectivity 3, 7. However, according to recent discoveries, POCs barely resorb bone matrix, on the contrary, they are beneficial for angiogenesis through secreting platelet derived growth factor‐BB (PDGF‐BB) 8, 9, 10.…”

Section: Introductionmentioning

confidence: 99%

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Graphene‐Based MicroRNA Transfection Blocks Preosteoclast Fusion to Increase Bone Formation and Vascularization

et al. 2017

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The objective of this study is to design a graphene‐based miRNA transfection drug delivery system for antiresorptive therapy. An efficient nonviral gene delivery system is developed using polyethylenimine (PEI) functionalized graphene oxide (GO) complex loaded with miR‐7b overexpression plasmid. GO‐PEI complex exhibits excellent transfection efficiency within the acceptable range of cytotoxicity. The overexpression of miR‐7b after GO‐PEI‐miR‐7b transfection significantly abrogates osteoclast (OC) fusion and bone resorption activity by hampering the expression of an essential fusogenic molecule dendritic cell‐specific transmembrane protein. However, osteoclastogenesis occurs without cell–cell fusion and preosteoclast (POC) is preserved. Through preservation of POC, GO‐PEI‐miR‐7b transfection promotes mesenchymal stem cell osteogenesis and endothelial progenitor cells angiogenesis in the coculture system. Platelet‐derived growth factor‐BB secreted by POC is increased by GO‐PEI‐miR‐7b both in vitro and in vivo. In treating osteoporotic ovariectomized mice, GO‐PEI‐miR‐7b significantly enhances bone mineral density, bone volume as well as bone vascularization through increasing CD31hiEmcnhi cell number. This study provides a cell–cell fusion targeted miRNA transfection drug delivery strategy in treating bone disorders with excessive osteoclastic bone resorption.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Graphene‐Based MicroRNA Transfection Blocks Preosteoclast Fusion to Increase Bone Formation and Vascularization

et al. 2017

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“…(38) Delta-Cq values >7 indicated high risk of hemolysis. Homogeneous efficiencies in RNA isolation were confirmed by RNA spike-in data (UniSp2, 4,5). In addition, the robustness of cDNA synthesis and absence of PCR inhibitors was confirmed by all samples by analyzing Cq values obtained of cDNA spike-in controls (UniSp6, cel-miR-39-3p).…”

Section: Quality Assurance For Entire Mirna Workflow and Hemolysis Tementioning

confidence: 63%

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

Heilmeier

Hackl²,

Skalicky

et al. 2016

Journal of Bone and Mineral Research

118

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Standard DXA measurements, including Fracture Risk Assessment Tool (FRAX) scores, have shown limitations in assessing fracture risk in Type 2 Diabetes (T2D), underscoring the need for novel biomarkers and suggesting that other pathomechanisms may drive diabetic bone fragility. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity and were recently found to be crucial to bone homeostasis and T2D. Here, we studied, if and which circulating miRNAs or combinations of miRNAs can discriminate best fracture status in a well-characterized study of diabetic bone disease and postmenopausal osteoporosis (n ¼ 80 postmenopausal women). We then tested the most discriminative and most frequent miRNAs in vitro. Using miRNA-qPCR-arrays, we showed that 48 miRNAs can differentiate fracture status in T2D women and that several combinations of four miRNAs can discriminate diabetes-related fractures with high specificity and sensitivity (area under the receiver-operating characteristic curve values [AUCs], 0.92 to 0.96; 95% CI, 0.88 to 0.98). For the osteoporotic study arm, 23 miRNAs were fracture-indicative and potential combinations of four miRNAs showed AUCs from 0.97 to 1.00 (95% CI, 0.93 to 1.00). Because a role in bone homeostasis for those miRNAs that were most discriminative and most present among all miRNA combinations had not been described, we performed in vitro functional studies in human adipose tissue-derived mesenchymal stem cells to investigate the effect of miR-550a-5p, miR-188-3p, and miR-382-3p on osteogenesis, adipogenesis, and cell proliferation. We found that miR-382-3p significantly enhanced osteogenic differentiation (p < 0.001), whereas miR-550a-5p inhibited this process (p < 0.001). Both miRNAs, miR-382-3p and miR-550a-5p, impaired adipogenic differentiation, whereas miR-188-3p did not exert an effect on adipogenesis. None of the miRNAs affected significantly cell proliferation. Our data suggest for the first time that miRNAs are linked to fragility fractures in T2D postmenopausal women and should be further investigated for their diagnostic potential and their detailed function in diabetic bone.

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“…31,82e85 In fact, in recognition of the importance of Wnt signaling in bone disease in humans, antibodies against two endogenous Wnt pathway inhibitors, sclerostin and DKK-1, are currently in Phase 2 clinical trials in osteoporosis. 85 Additionally, ligand activators of PPARg, such as the antidiabetic drug class thiazolidinediones, induce adipogenesis and osteoclastogenesis, 86 whereas PPARG haploinsufficiency increases osteoblastogenesis over adipogenesis. 87 Meanwhile, Wnt signaling promotion can decrease osteoclastogenesis.…”

Section: Potential Applications For Nell-1 In the Clinicmentioning

confidence: 99%

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

Shen

James

Zhang

et al. 2016

The American Journal of Pathology

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The differentiation factor NEL-like molecule-1 (NELL-1) has been reported as osteoinductive in multiple in vivo preclinical models. Bone morphogenetic protein (BMP)-2 is used clinically for skeletal repair, but in vivo administration can induce abnormal, adipose-filled, poorquality bone. We demonstrate that NELL-1 combined with BMP2 significantly optimizes osteogenesis in a rodent femoral segmental defect model by minimizing the formation of BMP2-induced adipose-filled cystlike bone. In vitro studies using the mouse bone marrow stromal cell line M2-10B4 and human primary bone marrow stromal cells have confirmed that NELL-1 enhances BMP2-induced osteogenesis and inhibits BMP2-induced adipogenesis. Importantly, the ability of NELL-1 to direct BMP2-treated cells toward osteogenesis and away from adipogenesis requires intact canonical Wnt signaling. Overall, these studies establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis. The novel abilities of NELL-1 to stimulate Wnt signaling and to repress adipogenesis may highlight new treatment approaches for bone loss in osteoporosis. NEL-like molecule-1 (NELL-1) is an osteoinductive growth factor first identified through its overexpression in pathologically fusing suture specimens from patients with craniosynostosis. 1,2 Transgenic Nell1-overexpressing mice recapitulate craniosynostosis-like phenotypes, exhibiting gross calvarial bone overgrowth and increased osteoblast differentiation. 3 Conversely, Nell1 deficiency severely disrupts bone growth, as mice with nonsense mutations in Nell1 die perinatally with major skeletal anomalies in the craniofacial complex, spine, and long bones. 4e6 Highlighting the central role of NELL-1 in skeletal development, NELL-1 mediates key downstream effects of the master osteogenic regulator runt-related transcription factor 2 (RUNX2) 7 and can partially rescue RUNX2 loss of function. 8 NELL-1 can also transiently activate mitogen-activated protein kinase signaling to induce RUNX2 phosphorylation and osteogenic differentiation. 9 Recently, we

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Osteoporosis: now and the future

Cited by 2,094 publications

References 94 publications

Graphene‐Based MicroRNA Transfection Blocks Preosteoclast Fusion to Increase Bone Formation and Vascularization

Graphene‐Based MicroRNA Transfection Blocks Preosteoclast Fusion to Increase Bone Formation and Vascularization

Serum miRNA Signatures Are Indicative of Skeletal Fractures in Postmenopausal Women With and Without Type 2 Diabetes and Influence Osteogenic and Adipogenic Differentiation of Adipose Tissue–Derived Mesenchymal Stem Cells In Vitro

Novel Wnt Regulator NEL-Like Molecule-1 Antagonizes Adipogenesis and Augments Osteogenesis Induced by Bone Morphogenetic Protein 2

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