Vascular calcification and osteolysis in diabetic neuropathy?is RANK-L the missing link?

Abstract

Diabetic neuropathy is associated with osteopenia and calcification of vascular smooth muscle cells. These changes are most marked in patients with acute neuropathic osteoarthropathy (Charcot foot), in which osteopenia is universal and the prevalence of vascular calcification exceeds 90%. While it has been thought that both osteopenia and vascular calcification may be linked to sympathetic denervation with increased peripheral limb perfusion, the cellular mechanism was not clear. However, the recent recognition that the receptor activator of nuclear factor kappa B ligand (RANK-L)/osteoprotegerin (OPG) signalling pathway is central to the processes regulating bone turnover in a wide variety of medical conditions has raised the possibility that the same cytokines may be involved in the osteolysis which accompanies diabetic neuropathy. This is made more likely by the realisation that the RANK-L/OPG pathway is also thought to mediate the calcification of vascular smooth muscle cells in coronary and peripheral vascular disease. The circumstantial evidence underpinning this hypothesis is reviewed here, and it is suggested that the unregulated activation of RANK-L-mediated effects on bone and arteries may be triggered by the loss of nerve-derived peptides, e.g. calcitonin gene-related peptide, which normally exert a moderating influence on the pathway. Keywords

Microvascular and C-Fiber Function in Diabetic Charcot Neuroarthropathy and Diabetic Peripheral Neuropathy

“…What is surprising is the relative preservation of MMH in the DCN groups, as this would be expected to be worse or similar to, but not significantly better than, the relatively less complicated DPN group. The latter findings are supported by other studies (13,14).…”

“…Bone dissolution, which is the hallmark of the condition, is dependent upon osteoclastic activativation by a system of cytokines, the receptor activator of the nuclear factor-B (NF-B) ligand (RANKL)-NF-B system (RANKL-NF-B) (10,12,13). This system is activated in diabetes (14 -16) and inhibited by neuropeptides (13).…”

“…This system is activated in diabetes (14 -16) and inhibited by neuropeptides (13). Thus, diabetic neuropathy may favor RANKL-NF-B system activation and may lead to protracted inflammation in CN (10).…”

Medial Arterial Calcification

“…However, the loss of nerve-derived peptides has been linked to an overactive RANKL/OPG axis to drive disease progression. Immunohistological analysis in Charcot foot patients has noted reduced expression of calcitonin gene-related peptide, 70 a neurotransmitter that modulates bone growth, repair, and remodeling in nociceptive C fibers. 71 Interestingly, calcitonin gene-related peptide is also known to have vasodilatory properties and the lack thereof is thought to contribute to age-related hypertrophy in rats.…”

Acute Neuropathic Joint Disease

“…Indeed, this was elegantly reviewed recently by Jeffcoate (17). In addition, several other compounds currently under investigation as inhibitors of ␣ v ␤ 3 integrin, which mediates adhesion of osteoclasts to bone surface, may have a role in this setting (18,19).…”