Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2

Jang, Won Gu; Kim, Eun Jung; Bae, In Ho; Lee, Kkot Nim; Kim, Yong Deuk; Kim, Don Kyu; Kim, Sun Hun; Lee, Chul‐Ho; Franceschi, Renny T.; Choi, Hueng Sik; Koh, Joon

doi:10.1016/j.bone.2010.12.003

Cited by 169 publications

(116 citation statements)

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“…These osteogenic effects could be mediated by an increase in COX-2 and endothelial nitric oxide synthase, in the activity of extracellular signalregulated kinases 1/2 as well as in BMP2 production (Hou et al 2008). Metformin was also found to regulate small heterodimer partner in MC3T3-E1 cells, an orphan nuclear receptor that stimulates osteoblastic bone formation by interacting with the transcription factor RUNX2 (Jang et al 2011). The action of metformin on bone marrow mesenchymal cell progenitors has also been investigated and metformin similarly causes an increase in ALP activity, collagen synthesis, osteocalcin production, and extracellular calcium deposition in vitro, possibly by increasing the expression of RUNX2 (Molinuevo et al 2010).…”

Section: Effect Of Ampk Activation On Bone Cell Activities In Vitro Amentioning

confidence: 99%

“…It was shown that AICAR and metformin both cause a direct osteogenic effect in MC3T3-E1 cells (Cortizo et al 2006, Kanazawa et al 2007, Jang et al 2011. These actions include a dose-dependent increase in cell proliferation, type I collagen production, alkaline phosphatase (ALP) activity, and mineral deposition.…”

Section: Effect Of Ampk Activation On Bone Cell Activities In Vitro Amentioning

confidence: 99%

“…Novel findings, described in detail in this review, have shown that AMPK plays a role in bone physiology. There are in vitro studies demonstrating that AMPK modulators regulate bone cell differentiation and function (Kanazawa et al 2007, Molinuevo et al 2010, Quinn et al 2010, Shah et al 2010, Jang et al 2011, Mai et al 2011 and two publications showing that deletions of AMPKa and b subunits in mice lead to bone loss in vivo (Quinn et al 2010, Shah et al 2010. Furthermore, AMPK activity can be regulated in bone cells by hormones, such as ghrelin and norepinephrine, that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues.…”

Section: Introductionmentioning

confidence: 99%

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AMP-activated protein kinase pathway and bone metabolism

Jeyabalan

Shah²,

Viollet³

et al. 2011

Journal of Endocrinology

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There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formation in vitro and the deletion of a or b subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis.

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Section: Effect Of Ampk Activation On Bone Cell Activities In Vitro Amentioning

confidence: 99%

Section: Effect Of Ampk Activation On Bone Cell Activities In Vitro Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AMP-activated protein kinase pathway and bone metabolism

Jeyabalan

Shah²,

Viollet³

et al. 2011

Journal of Endocrinology

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“…In part, this reflects an adverse effect of the latter-but there is growing reason to suspect that metformin and AMPK exert a favorable effect on bone density and structure. Metformin exposure in vitro prom o t e s o s t e o b l a s t i c d i f f e r e n t i a t i o n a n d behavior-increasing alkaline phosphatase activity and type 1 collagen production (Jang et al 2011;Cortizo et al 2006;Kanazawa et al 2008). These effects appear to be contingent on the AMPK-mediated induction of the short heterodimer partner orphan nuclear receptor cited above.…”

Section: Preserving Cartilage and Bonementioning

confidence: 95%

AMPK activation—protean potential for boosting healthspan

McCarty

2013

AGE

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AMP-activated kinase (AMPK) is activated when the cellular (AMP+ADP)/ATP ratio rises; it therefore serves as a detector of cellular "fuel deficiency." AMPK activation is suspected to mediate some of the health-protective effects of long-term calorie restriction. Several drugs and nutraceuticals which slightly and safely impede the efficiency of mitochondrial ATP g e n e r a t i o n -m o s t n o t a b l y m e t f o r m i n a n d berberine-can be employed as clinical AMPK activators and, hence, may have potential as calorie restriction mimetics for extending healthspan. Indeed, current evidence indicates that AMPK activators may reduce risk for atherosclerosis, heart attack, and stroke; help to prevent ventricular hypertrophy and manage congestive failure; ameliorate metabolic syndrome, reduce risk for type 2 diabetes, and aid glycemic control in diabetics; reduce risk for weight gain; decrease risk for a number of common cancers while improving prognosis in cancer therapy; decrease risk for dementia and possibly other neurodegenerative disorders; help to preserve the proper structure of bone and cartilage; and possibly aid in the prevention and control of autoimmunity. While metformin and berberine appear to have the greatest utility as clinical AMPK activators-as reflected by their efficacy in diabetes management-regular ingestion of vinegar, as well as moderate alcohol consumption, may also achieve a modest degree of healthprotective AMPK activation. The activation of AMPK achievable with any of these measures may be potentiated by clinical doses of the drug salicylate, which can bind to AMPK and activate it allosterically.

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“…Recent studies have shown that metformin can decrease fracture risk in patients with diabetes (Vestergaard et al 2005). In addition, metformin can induce the osteogenic differentiation of MC3T3E1 cells (clonal osteoblast-like cells derived from mouse calvaria) and bone marrow (BM) progenitor cells (Gao et al 2010;Jang et al 2011). However, the effect of metformin on the differentiation of human chorionic villous mesenchymal stem cells (CV-MSCs) is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Metformin Enhances Osteogenesis and Suppresses Adipogenesis of Human Chorionic Villous Mesenchymal Stem Cells

Yang

et al. 2017

Tohoku J. Exp. Med.

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Metformin is the first-line anti-hyperglycemic drugs commonly used to treat type 2 diabetes. Recent studies have shown that metformin can enhance bone formation through induction of endothelial nitric oxide synthase (eNOS). Human chorionic villous mesenchymal stem cells (CV-MSCs) are promising candidates for regenerative medicine. The present study aimed to investigate the effects of metformin on the osteogenic and adipocytic differentiation of human CV-MSCs, and to elucidate the underlying mechanism. CV-MSCs, prepared from human term placentae, were cultured with different concentrations of metformin. Treatment for 72 hours with 0.05 mM metformin had no noticeable effect on the proliferation of CV-MSCs. Consequently, CV-MSCs were cultured for seven or 14 days in the osteogenic medium supplemented with 0.05 mM metformin. Treatment for seven days with metformin increased the expression levels of osteogenic protein mRNAs, including alkaline phosphatase, runt-related transcription factor 2, and osteopontin. Metformin also enhanced the mineralization of CV-MSCs. Furthermore, metformin induced the expression of eNOS in CV-MSCs during osteogenic differentiation. By contrast, when CV-MSCs were cultured for 14 days in the adipogenic medium, 0.05 mM metformin inhibited the expression of adipogenic protein mRNAs, including proliferators-activated receptor-γ and CCAAT/enhancer binding protein-α. The lipid droplet accumulation was also reduced on 28 days after metformin treatment. These findings indicate that metformin can enhance osteogenic differentiation of CV-MSCs and reduce adipocyte formation. The effect of metformin on osteogenic differentiation of CV-MSCs may be associated with eNOS expression. Our findings will highlight the therapeutic potential of metformin in osteoporosis and bone fracture.

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Metformin induces osteoblast differentiation via orphan nuclear receptor SHP-mediated transactivation of Runx2

Cited by 169 publications

References 55 publications

AMP-activated protein kinase pathway and bone metabolism

AMP-activated protein kinase pathway and bone metabolism

AMPK activation—protean potential for boosting healthspan

Metformin Enhances Osteogenesis and Suppresses Adipogenesis of Human Chorionic Villous Mesenchymal Stem Cells

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