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Molecular Modulation of Osteoblasts and Osteoclasts in Type 2 Diabetes 时间:2018-11-08 13:14 来源:未知作者:admin 点击: 次 Abstract:Diabetes is a common disease affecting majority of populations worldwide. Since 1980, there has been an increase in the number of people diagnosed as prediabetic and diabetic. Diabetes is characterized by high levels of circulating glucose and leads to most microvascular and macrovascular complications such as retinopathy, nephropathy, neuropathy, stroke, and myocardial infarction. Bone marrow vascular disruption and increased adiposity are also linked to various complications in type II diabetes mellitus. In addition to these complications, type 2 diabetic patients also have fragile bones caused by faulty mineralization mainly due to increased adiposity among diabetic patients that affects both osteoblast and osteoclast functions. Other factors that increase fracture risk in diabetic patients are increased oxidative stress, inflammation, and drugs administered to diabetic patients. This review reports the modulation of different pathways that affect bone metabolism in diabetic conditions.
1. Introduction
Diabetic patients are at high risk of developing osteoporosis. Normal to high bone mineral density (BMD) measurements recorded in type II diabetes mellitus (T2DM) patients are misleading [1]. In diabetic patients, an increase in the risk of hip (1.4–1.7-fold) and vertebral fractures have been reported [2]. As one ages, both genders are not only susceptible to increased risk of fragile bones but are also at high risk of developing diabetes, which augments the risk of bone fractures [3–6]. Bone fragility in T2DM patients is related to decreased bone strength and malformation of collagen fibers that can result in faulty mineralization and increased micro damages [7–9]. Using BMD measurements alone to diagnose bone condition in T2DM may not be reliable as the strength of the bone may be compromised in these patients. It is suggested that BMD with body mass index (BMI) adjustments may be a better indicator [10]. Supplemental data such as biochemical markers can be additional diagnostic tool. Bone biochemical markers such as C-terminal telopeptide (CTX) and N-terminal telopeptide (NTX) will reflect on the bone resorption process and breakdown of the collagen fibers. Interestingly, in T2DM patients, there is decreased CTX and increased NTX levels [11], and other reports did not find any difference between the two markers [12].
However, in T2DM patients, the quality of collagen fibers is compromised rather than increased breakdown of the collagen fibers. In T2DM patients, the trabecular bone network was shown to have large holes, decreased osteoblast recruitment, and mineral apposition rates combined with increased osteoclastogenesis [13].
The major pathophysiology in T2DM patients is insulin resistance (IR). This can be attributed to lack of or decreased insulin secretion and/or insulin receptors on the cell membranes. A close relationship between glucose and bone metabolism has been reported [14–18]. Yamaguchi and Sugimoto have described the link between glucose, fat, and bone metabolism [2]. They have suggested that osteocalcin, an important bone-forming marker, in the uncarboxylated form and the Wnt signalling pathway proteins, may be modulated to increase the fragility of bones in diabetic patients [19]. Other hormones secreted by adipocytes like adiponectin decrease IR [20], while leptin increases IR [21, 22]; moreover, advanced glycation end products (AGEs) and insulin-like growth factor-I (IGF-1), which regulate bones, may be also modified in T2DM [1, 2]. AGE is formed by elevated blood glucose levels that cause nonenzymatic glycosylation and binds to its receptor (RAGE) which activates transcription factor nuclear factor-κB (NF-κB). This results in increased expression of receptor activator of nuclear factor kappa-B ligand- (RANKL-) mediated osteoclastogenesis [23, 24]. Accumulation of AGE may also stimulate interleukins (IL) such as IL-6, which reduces osteoblast proliferation and activity while increasing osteoclastic activity [1, 25–29]. In T2DM patients, there is hypersecretion of calcium and decreased calcium absorption due to decreased vitamin D levels and estrogenic levels, especially in females [30].
In addition, drugs used to treat diabetes can also have an effect on bone health. One such group of drugs is thiazolidiones (TZD), which increases the risk of osteoporosis in T2DM patients. TZDs are capable of influencing the mesenchymal cells to differentiate more into adipocytes rather than osteoblasts which results in increased cortical porosity [31]. Furthermore, insulin is administered to diabetic patients to help lower circulating glucose which directly acts on osteoclasts. A review of the drug effects on bone can be found in Montagnani et al. [1]. Although metformin has been shown to reduce bone loss, based on the severity of the side effects caused by this drug [32], absorption of nutrients essential for bone health may be compromised [30].