Faisal E Al Jofi1, Tao Ma2, Dong Guo3, Monica P Schneider4, Yan Shu5, Hockin H K Xu6, Abraham Schneider7. 1. Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA; Department of Preventive Dental Science, Division of Periodontics, Imam Abdulrahman Bin Faisal University, College of Dentistry, Dammam, Saudi Arabia. 2. Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA. 3. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA. 4. Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Maryland, Baltimore, Maryland, USA. 5. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA; Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA. 6. Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA; Biomaterials and Tissue Engineering Division, Department of Advanced Oral Sciences and Therapeutics, School of Dentistry, University of Maryland, Baltimore, Maryland, USA; Center for Stem Cell Biology and Regenerative Medicine, School of Medicine, University of Maryland, Baltimore, Maryland, USA. 7. Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland, Baltimore, Maryland, USA; Greenebaum Comprehensive Cancer Center, Program in Oncology, School of Medicine, University of Maryland, Baltimore, Maryland, USA. Electronic address: schneider66@umaryland.edu.
Abstract
BACKGROUND: Compelling evidence indicates that metformin, a low-cost and safe orally administered biguanide prescribed to millions of type 2 diabetics worldwide, induces the osteoblastic differentiation of mesenchymal stromal cells (MSCs) through the 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway. As a highly hydrophilic cationic compound, metformin uptake is facilitated by cell membrane organic cation transporters (OCTs) of the solute carrier 22A gene family. We hypothesized that to effectively enhance osteogenic differentiation, and ultimately bone regeneration, metformin must gain access into functional OCT-expressing MSCs. METHODS: Data was obtained through immunoblotting, cellular uptake, mineralization and gene expression assays. RESULTS: We demonstrate for the first time that functional OCTs are expressed in human-derived MSCs from umbilical cord Wharton's jelly, an inexhaustible source of nonembryonic MSCs with proven osteogenic potential. A clinically relevant concentration of metformin led to AMPK activation, enhanced mineralized nodule formation and increased expression of the osteogenic transcription factor Runt-related transcription factor 2 (RUNX2). Indeed, targeting OCT function through pharmacological and genetic approaches markedly blunted these responses. CONCLUSIONS: Our findings indicate that functional OCT expression in UC-MSCs is a biological prerequisite that facilitates the intracellular uptake of metformin to induce an osteogenic effect. Future pre-clinical studies are warranted to investigate whether the expression of functional OCTs may serve as a potential biomarker to predict osteogenic responses to metformin.
BACKGROUND: Compelling evidence indicates that metformin, a low-cost and safe orally administered biguanide prescribed to millions of type 2 diabetics worldwide, induces the osteoblastic differentiation of mesenchymal stromal cells (MSCs) through the 5' adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway. As a highly hydrophilic cationic compound, metformin uptake is facilitated by cell membrane organic cation transporters (OCTs) of the solute carrier 22A gene family. We hypothesized that to effectively enhance osteogenic differentiation, and ultimately bone regeneration, metformin must gain access into functional OCT-expressing MSCs. METHODS: Data was obtained through immunoblotting, cellular uptake, mineralization and gene expression assays. RESULTS: We demonstrate for the first time that functional OCTs are expressed in human-derived MSCs from umbilical cord Wharton's jelly, an inexhaustible source of nonembryonic MSCs with proven osteogenic potential. A clinically relevant concentration of metformin led to AMPK activation, enhanced mineralized nodule formation and increased expression of the osteogenic transcription factor Runt-related transcription factor 2 (RUNX2). Indeed, targeting OCT function through pharmacological and genetic approaches markedly blunted these responses. CONCLUSIONS: Our findings indicate that functional OCT expression in UC-MSCs is a biological prerequisite that facilitates the intracellular uptake of metformin to induce an osteogenic effect. Future pre-clinical studies are warranted to investigate whether the expression of functional OCTs may serve as a potential biomarker to predict osteogenic responses to metformin.
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