RANKL-RANK-OPG Pathway in Charcot Diabetic Foot: Pathophysiology and Clinical-Therapeutic Implications

Abstract

Charcot Foot (CF), part of a broader condition known as Charcot Neuro-Osteoarthropathy (CNO), is characterized by neuropathic arthropathy with a progressive alteration of the foot. CNO is one of the most devastating complications in patients with diabetes mellitus and peripheral neuropathy but can also be caused by neurological or infectious diseases. The pathogenesis is multifactorial; many studies have demonstrated the central role of inflammation and the Receptor Activator of NF-κB ligand (RANKL)-Receptor Activator of NF-κB (RANK)-Osteoprotegerin (OPG) pathway in the acute phase of the disease, resulting in the serum overexpression of RANKL. This overexpression and activation of this signal lead to increased osteoclast activity and osteolysis, which is a prelude to bone destruction. The aim of this narrative review is to analyze this signaling pathway in bone remodeling, and in CF in particular, to highlight its clinical aspects and possible therapeutic implications of targeting drugs at different levels of the pathway. Drugs that act at different levels in this pathway are anti-RANKL monoclonal antibodies (Denosumab), bisphosphonates (BP), and calcitonin. The literature review showed encouraging data on treatment with Denosumab, although in a few studies and in small sample sizes. In contrast, BPs have been re-evaluated in recent years in relation to the high possibility of side effects, while calcitonin has shown little efficacy on CNO.

Effectiveness of Pamidronate Infusion in the Treatment of Charcot Arthropathy

“…This overexpression and activation of this signal lead to increased osteoclast activity and osteolysis, which is a prelude to bone destruction. Drugs that act at different levels in this pathway are anti-RANKL monoclonal antibodies (Denosumab), bisphosphonates (BP), and calcitonin 12 , 13 .…”

Charcot arthropathy of the knee accompanied by tethered cord syndrome and lumbosacral fur sinus

“…It has been reported that inflammation is particularly critical in the pathogenesis. The imbalance of OPG/RANKL/RANK signaling pathway promotes osteoclast maturation and osteoblast decay, and aggravates inflammatory reaction, which is one of the important mechanisms leading to Charcot's joint [ 6 ]. This patient has a history of congenital spina bifida meningocele complicated with tethered cord syndrome and fur sinus, so the etiology was considered to be a combination of factors.…”

Overview of Ankle Arthropathy in Hereditary Hemochromatosis

“…Antioxidants : these have been shown in in vitro studies to protect osteoclasts and osteoblasts from oxidative-stress-induced abnormalities resulting from iron overload [ 53 ]; furthermore, reducing oxidative stress can prevent chondrocyte damage and cartilage degeneration [ 54 ]. For example, N-acetylcysteine (NAC) can protect chondrocytes from oxidative stress caused by Interleukin 1, which is also responsible for chondrocyte apoptosis [ 53 , 56 ].…”