Inhibitory effect of metformin on bone metastasis of cancer via OPG/RANKL/RANK system

Wang, Jian; Chen, Tianyu; Qin, Si; Duan, Yan; Wang, Gang

doi:10.1016/j.mehy.2013.08.032

Cited by 13 publications

(12 citation statements)

References 23 publications

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“…Given that AMPK is a regulator of cellular energy sensing, a role for metformin in stimulating osteogenesis and inhibiting adipogenesis is conceptually consistent with its presumed systemic effects . Metformin is also hypothesized to be a negative regulator of receptor activator of nuclear factor kappa‐Β ligand (RANKL), inhibiting the differentiation of osteoclasts . Additionally, metformin has been shown to be a negative regulator of chondrocyte differentiation …”

Section: Drugs and Bonementioning

confidence: 93%

“…127 Metformin is also hypothesized to be a negative regulator of receptor activator of nuclear factor kappa-Β ligand (RANKL), inhibiting the differentiation of osteoclasts. 128,129 Additionally, metformin has been shown to be a negative regulator of chondrocyte differentiation. 130 Nevertheless, not all in vitro studies support an anabolic role for metformin.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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Summary Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age‐matched persons without diabetes, attributed to disease‐specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin‐based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall‐related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo‐anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium‐dependent glucose co‐transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes‐related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

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Section: Drugs and Bonementioning

confidence: 93%

Section: Mechanism Of Actionmentioning

confidence: 99%

Diabetes pharmacotherapy and effects on the musculoskeletal system

Kalaitzoglou

Fowlkes

Popescu

et al. 2018

Diabetes Metabolism Res

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“…By binding to RANKL, OPG inhibits the interaction of RANKL-RANK, thereby preventing RANK activation and subsequent osteoclastogenesis 13 . This system has also been reported to play roles in several cellular functions, which include apoptotic effect, immune response maintainance, and carcinogenesis 14,15 . Recently, studies showed that human OA chondrocytes also express and produce OPG, RANKL and RANK, and the molecular triad appears to be involved in OA progression 16 .…”

mentioning

confidence: 99%

The effects of chitosan oligosaccharides on OPG and RANKL expression in a rat osteoarthritis model

Zhang

Jiang

et al. 2017

Acta Cir. Bras.

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Purpose: To investigate the effect of chitosan oligosaccharides (COS) against osteoarthritis (OA) and preliminarily discuss the osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL) and RANK expression in a rat OA model. Methods: Thirty-six 6-week-old Male SD rats were randomly divided into three groups: shamoperated group(CON), OA-induction group(OA), COS intervention group(n=12/group). At 4 weeks after the operation, COS (50 ul) intervention weekily for consecutive 5 weeks. The OA and CON groups received an injection of 50 ul physiological saline. At death, 11 weeks following surgery, cartilage was harvested and total RNA and protein were extracted. Both the morphological changes of the cartilage were observed and harvested the total RNA and protein.Meanwhile, the expression of OPG, RANKL and RANK in cartilage were determined. Results: The expression of OPG and RANKL were both enhanced in the cartilage of the OA model. Compared with the OA group, COS treatment improved the cartilage damage (both extent and grade). Furthermore, the COS group showed highly OPG and lower RANKL. Simultaneously, COS treatment upregulated the ratio of OPG/RANKL and downregulated the RANKL/RANK. Conclusion: Chitosan oligosaccharides may be used as a unique biological agent to prevent and treat osteoarthritis, and this effect is associated with modulation of the expression of osteoprotegerin and receptor activator of NF-κB ligand.

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“…Studies on the effects of OPG on bone resorption by osteoclasts have focused mainly on the OPG-induced inhibition of osteoclast differentiation through the OPG/receptor activator of the nuclear factor kappa-B ligand (RANKL)/RANK system (22)(23)(24). It has been reported that OPG promotes the separation of osteoclasts adhering to the bone matrix from the bone surface (25).…”

Section: Inhibition Of Osteoclast Bone Resorption Activity Through Osmentioning

confidence: 99%

Inhibition of osteoclast bone resorption activity through osteoprotegerin-induced damage of the sealing zone

Song

Zhu

et al. 2014

International Journal of Molecular Medicine

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Bone remodeling is dependent on the dynamic equilibrium between osteoclast-mediated bone resorption and osteoblast-mediated osteogenesis. The sealing zone is an osteoclast-specific cytoskeletal structure, the integrity of which is critical for osteoclast-mediated bone resorption. To date, studies have focused mainly on the osteoprotegerin (OPG)‑induced inhibition of osteoclast differentiation through the OPG/receptor activator of the nuclear factor kappa-B ligand (RANKL)/RANK system, which affects the bone resorption of osteoclasts. However, the effects of OPG on the sealing zone have not been reported to date. In this study, the formation of the sealing zone was observed by Hoffman modulation contrast (HMC) microscopy and confocal laser scanning microscopy. The effects of OPG on the existing sealing zone and osteoclast-mediated bone resorption activity, as well as the regulatory role of genes involved in the formation of the sealing zone were examined by immunofluorescence staining, HMC microscopy, quantitative reverse transcription polymerase chain reaction (RT-qPCR), western blot analysis and scanning electron microscopy. The sealing zone was formed on day 5, with belt-like protuberances at the cell edge and scattered distribution of cell nuclei, but no filopodia. The sealing zone was intact in the untreated control group. However, defects in the sealing zone were observed in the OPG-treated group (20 ng/ml) and the structure was absent in the groups treated with 40 and 80 ng/ml OPG. The podosomes showed a scattered or clustered distribution between the basal surface of the osteoclasts and the well surface. Furthermore, resorption lacunae were not detected in the 20 ng/ml OPG-treated group, indicating the loss of osteoclast-mediated bone resorption activity. Treatment with OPG resulted in a significant decrease in the expression of Arhgef8/Net1 and DOCK5 Rho guanine nucleotide exchange factors (RhoGEFs), 10 of 18 RhoGTPases (RhoA, RhoB, cdc42v1, cdc42v2, RhoU/Wrch1, RhoF/Rif, Rac2, RhoG, Rnd1 and RhoBTB1), ROCK1 and ROCK2. In conclusion, podosome distribution was affected by the OPG-induced inhibition of the expression of genes in the RhoGTPase signaling pathway. This resulted in damage to or destruction of the sealing zone, thus inhibiting osteoclast-mediated bone resorption activity.

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Inhibitory effect of metformin on bone metastasis of cancer via OPG/RANKL/RANK system

Cited by 13 publications

References 23 publications

Diabetes pharmacotherapy and effects on the musculoskeletal system

Diabetes pharmacotherapy and effects on the musculoskeletal system

The effects of chitosan oligosaccharides on OPG and RANKL expression in a rat osteoarthritis model

Inhibition of osteoclast bone resorption activity through osteoprotegerin-induced damage of the sealing zone

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