Neuropathy and the vascular-bone axis in diabetes: lessons from Charcot osteoarthropathy

Emerging evidence from the last two decades has shown that vascular calcification (VC) is a regulated, cell-mediated process orchestrated by vascular smooth muscle cells (VSMCs) and that this process bears many similarities to bone mineralization. While many of the mechanisms driving VSMC calcification have been well established, it remains unclear what factors in specific disease states act to promote vascular calcification and in parallel, bone loss. Diabetes is a condition most commonly associated with VC and bone abnormalities. In this review, we describe how factors associated with the diabetic milieu impact on VSMCs, focusing on the role of oxidative stress, inflammation, impairment of the advanced glycation end product (AGE)/receptor for AGE system and, importantly, diabetic neuropathy. We also explore the link between bone and VC in diabetes with a specific emphasis on the receptor activator of nuclear factor κβ ligand/osteoprotegerin system. Finally, we describe what insights can be gleaned from studying Charcot osteoarthropathy, a rare complication of diabetic neuropathy, in which the occurrence of VC is frequent and where bone lysis is extreme.     

Bone-vascular cross-talk

Increasing numbers of cross-sectional studies on general populations and chronic kidney disease (CKD) or end-stage renal disease (ESRD) patients have reported relationships between cardiovascular calcifications and bone disorders, including osteoporosis, osteopenia and high or low bone activity. The mechanisms underlying this bone-cardiovascular axis and biological links between bone and arterial abnormalities are suggestive of bone-vascular cross-talk. The nature of these links is not well understood and could result from: 1) common factors acting on bone remodeling and arterial calcification; 2) compromised bone blood supply responsible for arteriosclerosis of bone vessels and reduced perfusion; and/or 3) direct action of bone cells (osteoblasts/osteocytes) on vascular biology and structure. Inflammation and accumulation of reactive oxygen species are the principal common pathways linking bone and arterial pathologies.     

Pathogenesis and management of vascular calcification in CKD and dialysis patients

Patients with chronic kidney disease (CKD) have a predisposition to develop vascular calcification due to dysregulated homeostatic mechanisms, which lead to an imbalance in the circulatory promoters and inhibitors of vascular calcification, leading to a net calcification stress. These factors promote ectopic calcification and induce vascular smooth muscle cells to undergo osteogenic differentiation and actively calcify the vascular media. The article summarizes clinically relevant pathogenic mechanisms of vascular calcification in patients with CKD and in dialysis patients and summarizes novel therapeutic interventions. In addition to the management of traditional cardiovascular risk factors, patients with CKD‐mineral and bone disorder need close attention in the management of the mineral metabolism to prevent adverse effects on the bone and vascular compartments. This article reviews current evidence and therapeutic guidelines in the management of mineral metabolism in CKD and dialysis.     

Regulation of In Vitro Vascular Calcification by BMP4, VEGF and Wnt3a

Vascular calcification is a common clinical complication of cardiovascular disease, diabetes and end-stage renal failure, associated with significant morbidity and mortality. In this study we demonstrate that factors secreted by the hypertrophic chondrocytes induce matrix mineralization and osteoblastic transformation in cultured mouse vascular smooth muscle cells (VSMCs). In addition, these factors render VSMCs responsive to BMP4 and Wnt3a ligands. Neither BMP-4 nor Wnt3a could induce mineralization in short-term (up to 8 days) cultures of primary mouse VSMCs. However, both ligands act synergistically with the chondrocyte-conditioned medium causing a further increase in VSMC calcification. Finally, we show that commitment of VSMCs towards the BMP-regulated mineralization can be induced by the chondrocyte-secreted bone anabolic factor VEGF. In addition, expression profiling suggests a novel role in vascular calcification for the matrix proteins previously known to regulate bone formation and mineralization (including MMP3, fibulin, 11betahydroxysteroid dehydrogenase 1 and retinoic acid receptor responder 2). The results of this study may contribute to further understanding of the cellular mechanisms responsible for vascular calcification and provide important information for the treatment of this pathology.     

骨质疏松与血管钙化

骨质疏松症与血管钙化是严重威胁中老年人健康的两类重要疾病,通常认为它们与增龄相关且相互独立,但越来越多的临床和基础研究表明,二者密切联系,且可能拥有共同的危险因素,并受同样的通路、蛋白质和激素等的调控,包括RANKLRANK-OPG通路、Wnt通路及甲状旁腺激素等。典型Wnt通路的抑制剂硬骨素不仅在骨重建中发挥着关键作用,在血管钙化中也扮演着重要角色。研究发现,血管钙化发生时,血管平滑肌细胞发生骨样细胞转分化并分泌硬骨素,但硬骨素在血管钙化中起到保护或损害作用仍存在争议。近期临床研究表明,靶向Wnt通路、用于治疗骨质疏松症的硬骨素抗体(罗莫单抗)具有促进骨形成和抑制骨吸收的双重作用,其治疗效果优于其他抗骨质疏松药物;但第三期临床试验发现,其会增加心血管疾病的患病风险,而其机制尚不清楚,有待深入研究。总之,研究骨质疏松和血管钙化之间关系及其共性机制,对避免某种特异性药物的不良反应、以及同时防治两种疾病有重要意义。     

Vascular calcification

PURPOSE OF REVIEW: Accumulating evidence suggests that the high cardiovascular mortality observed in patients with end-stage renal disease is due in part to the deleterious effects of vascular calcification that develops over time on dialysis. This review focuses on recent cell biological and animal studies that have shed light on the mechanisms and regulators of vascular smooth muscle cell calcification in end-stage renal disease. RECENT FINDINGS: Clinical studies demonstrate that high circulating levels of phosphate or calcium predict vascular calcification. Recent cell biological studies have provided novel insights into how vascular smooth muscle cells regulate calcification in response to such insults. Vascular smooth muscle cell damage and subsequent vesicle release from viable and dying cells create an environment permissive for the nucleation of basic calcium phosphate mineral. This, combined with osteogenic conversion of vascular smooth muscle cells and consequent loss of their normal inhibitory processes/pathways, results in calcification. Circulating factors such as fetuin-A, with the potential to impact on vessel wall calcification, have also been identified. Animal studies suggest that the 'uremic milieu' potentiates calcification and have clearly established a link between vascular calcification and bone metabolism. However, our understanding of the factors that contribute to vascular smooth muscle cell calcification in end-stage renal disease remains incomplete. SUMMARY: Systematic studies are required that integrate epidemiological studies to identify risk factors with in-vitro experiments to investigate mechanisms leading to vascular smooth muscle cell calcification in response to these factors. Animal and clinical studies can subsequently be used to assess how modifying risk factors under the complex physiological conditions of end-stage renal disease impacts on vessel wall health.     

Soft bone - hard arteries: a link?

Chronic kidney disease is characterized by mineral and various bone disorders associated with extraosseous and cardiovascular calcifications. Experimental studies and clinical observations in the general population and in chronic kidney disease patients show an inverse relationship between the extent of cardiovascular calcifications and bone mineral density or bone metabolic activity. Arterial calcification and osteoporosis are frequently observed in the same subjects and progress in parallel in postmenopausal women, and associations between histomorphometric indices of bone activity and vascular calcifications were also observed in patients with chronic and end-stage kidney diseases. The biological linkage between vascular calcifications and bone changes is certainly a part of the aging process, but in many studies these bone-vascular associations remained significant after adjustment for age, which suggests an age-independent causal relationship. Based on clinical and experimental evidence showing an association between bone disorders and functional and structural changes of the arterial system the concept of a bone-vascular axis was established complementary to the classical kidney-bone axis. Nevertheless, the factors or mechanisms accounting for these associations are not well understood, and could result from (1) arterial disease responsible for bone abnormalities; (2) action of common dysmetabolic or 'toxic' factors and mechanisms acting on bones and vessels, or (3) direct or indirect influence of bone cells and metabolism on the arterial system. This short review aims to illustrate these possible mechanisms.     

The role of osteoprogenitors in vascular calcification

Calcification is a component of vascular disease that usually occurs in concert with atheroma formation but through distinct pathophysiological processes. Vessel wall osteoprogenitor cells known as calcifying vascular cells can form bone matrix proteins and calcified nodules, analogous to osteoblastic differentiation in bone. These cells have been isolated from the tunica media of bovine and human arteries, and both in-vitro tissue culture models and mouse models of vascular calcification have been established. Studies of the effects of diabetes mellitus, hyperlipidemia, estrogens and glucocorticoids on calcifying vascular cell function provide insight into the relationship between common human disease states and vascular calcification.     

Mechanisms of vascular calcification in chronic kidney disease

Vascular calcification is common in chronic kidney disease and associated with increased morbidity and mortality. Its mechanism is multifactorial and incompletely understood. Patients with chronic kidney disease are at risk for vascular calcification because of multiple risk factors that induce vascular smooth muscle cells to change into a chondrocyte or osteoblast-like cell; high total body burden of calcium and phosphorus due to abnormal bone metabolism; low levels of circulating and locally produced inhibitors; impaired renal excretion; and current therapies. Together these factors increase risk and complicate the management of vascular calcification.