Metformin Carbon Dots for Promoting Periodontal Bone Regeneration via Activation of ERK/AMPK Pathway

Abstract

The osteogenic potential of mesenchymal stem cells (MSCs) is severely impaired under persistent inflammation of periodontitis. A highly efficient way to promote or rescue osteogenic potential of MSCs under inflammation remains an unmet goal. Herein, metformin carbon dots (MCDs) with excellent biocompatibility are prepared from metformin hydrochloride and citric acid via a hydrothermal method. The MCDs can more effectively enhance the alkaline phosphatase (ALP) activity, calcium deposition nodules formation, expression of osteogenic genes and proteins in rat bone marrow mesenchymal stem cells (rBMSCs) than metformin under both inflammatory and normal conditions. Moreover, a novel pathway of extracellular signal‐regulated kinases (ERK)/AMP‐activated protein kinase (AMPK) signaling is involved in the MCDs‐induced osteogenesis. In periodontitis rats, MCDs can effectively regenerate the lost alveolar bone, but not the metformin. Taken together, MCDs can be the promising candidate nanomaterial for periodontitis treatment. This work may provide a new pharmacological target of ERK/AMPK pathway for treating bone loss and also give additional insights into developing nanodrugs from the numerous medications.

The Potential Therapeutic Role of Metformin in Diabetic and Non-Diabetic Bone Impairment

“…Previous studies showed that metformin had a potentially positive effect on 20% reductions of fracture risk in T2DM patients [ 115 ]. In addition, metformin is indirectly involved in the action of ERK activation and the induction of inducible nitric oxide synthase (iNOS), both of which are an important regulative factor in osteogenesis [ 68 ]. Since metformin has no substantial effect or side effect on the control of glucose levels in nondiabetic individuals, it may be regarded as a potential adjuvant therapeutic drug for bone disorders in patients without diabetes.…”

“…It is well known that the osteogenic potential of mesenchymal stem cells (MSCs) is seriously affected by persistent inflammation of periodontitis. Metformin carbon dots (MCDs) including citric acid and metformin hydrochloride effectively improved the activity of ALP, the formation of calcium deposition nodules, the expression of genes and osteogenic proteins in mesenchymal stem cells of the rat bone marrow (rBMSCs), thereafter effectively helped to regenerate lost alveolar bone in periodontitis rats [ 68 ]. A recent study showed that polycaprolactone/chitosan nanofibrous membranes containing metformin would be favored for bone regeneration as guided bone regeneration membranes because it was more suitable for cell proliferation, adhesion, and osteogenic differentiation of rBMSCs [ 69 ].…”

Nanomaterials in Bone Regeneration

“…The preparation of CDs is very simple and economically undemanding. CDs coated with metformin activated the ERK/AMPK pathway and promoted periodontal bone regeneration [206]. CDs significantly enhanced matrix mineralization, promoted osteogenic differentiation in vitro, and stimulated new bone growth in the skull defect model in vivo [207].…”

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

“…Min-Ji Ahn and Goang-Won Cho indicated, in a research conducted in 2017, that activation of AMPK by metformin could have a stimulatory role in human bone marrow mesenchymal stem cells towards neural differentiation (Ahn and Cho 2017 ). Various studies have shown that treatment with metformin is effective in bone structure, including osteoarthritis (Feng et al 2020 ; Li et al 2020a , b ; Li et al 2020a , b ), osteoporosis (Blümel et al 2020 , Guo et al 2022 , Song et al 2022 ), bone regeneration (Ren et al 2021 ; Fang et al 2022 ; Sun et al 2022 ) and osteosarcoma (Paiva-Oliveira et al 2018 ; Zhao et al 2019 , Lu et al 2021 ).…”