Abstract
Type 2 diabetes mellitus (T2DM) and osteoarthritis (OA) are common chronic diseases that frequently co-exist. The link between OA and T2DM is attributed to common risk factors, including age and obesity. Several reports suggest that hyperglycemia and accumulated advanced glycosylation end-products might regulate cartilage homeostasis and contribute to the development and progression of OA. Metformin is used widely as the first-line treatment for T2DM. The drug acts by regulating glucose levels and improving insulin sensitivity. The anti-diabetic effects of metformin are mediated mainly via activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is an energy sensing enzyme activated directly by an increase in the AMP/ATP ratio under conditions of metabolic stress. Dysregulation of AMPK is strongly associated with development of T2DM and metabolic syndrome. In this review, we discuss common risk factors, the association between OA and T2DM, and the role of AMPK. We also address the adaptive use of metformin, a known AMPK activator, as a new drug for treatment of patients with OA and T2DM.
Highlights
Several studies show marked regulation of ADAMTS-4 and ADAMTS-5 after stimulation with tumor necrosis factor-α (TNF-α) and oncostatin M, as well as IL-1-induced expression of ADANTS-4, by both human and mouse chondrocytes [60,61]. Both mechanical stress and inflammatory mediators induce NF-κB (p65/p50)- and activate mitogen-induced protein kinase (MAPK)-mediated downstream signaling pathways, which are abnormally activated in osteoarthritic chondrocytes [62]
Leptin regulates cartilage homeostasis by influencing osteoblast proliferation and differentiation, as well as by suppressing bone formation through a hypothalamic relay. Another adipokine expressed in adipose tissue, adiponectin, plays a role in cartilage hemostasis by increasing expression of tissue inhibitor of metalloprotease-2 (TIMP-2), and by decreasing IL-1β-induced expression of matrix metalloproteinases (MMPs)-3, in chondrocytes [78]
Typical factors associated with central obesity and metabolic syndrome (MetS) induce pro-inflammatory macrophage polarization and activity within synovial and adipose tissue; these phenomena occur via alterations in AMP-activated protein kinase (AMPK) and mTORC1 expression, as well as changes in adipokine levels
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Osteoarthritis (OA) and type 2 diabetes mellitus (T2DM) are common chronic diseases worldwide. Rates of T2DM have increased markedly since 1960; 12% of adults aged 20 years and above, and 26% of those over 65, are affected [4]. The molecular mechanism(s) underlying the high prevalence of OA in those with T2DM is not clear, OA and T2DM share risk factors such as aging and obesity. Degradation of the ECM results in gradual impairment of articular cartilage function, usually accompanied by pain and physical disability [13]. Between 2001 and 2009, the prevalence increased markedly worldwide, in parallel with obesity It begins in middle or older age, the rates in children and adolescents in five areas of the USA were around 21% [22,23,24]. Mitochondrial dysfunction is related to insulin resistance (reduced uptake and sensitivity of tissues to glucose) [28]
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