Proinflammatory Modulation of the Surface and Cytokine Phenotype of Monocytes in Patients With Acute Charcot Foot

Abstract

OBJECTIVEDespite increased information on the importance of an inappropriate inflammatory response in the acute Charcot process, there has been no previous attempt to define the specific pathways that mediate its pathogenesis. Here, the role played by monocytes was analyzed.RESEARCH DESIGN AND METHODSThe immune phenotype of peripheral monocytes was studied by fluorescence-activated cell sorter analysis comparing patients with acute Charcot (n = 10) in both the active and recovered phase, diabetic patients with neuropathy (with or without osteomyelitis), and normal control subjects.RESULTSWhen compared with diabetic control subjects and healthy subjects, monocytes from acute Charcot patients showed a proinflammatory immune phenotype characterized by increased production of proinflammatory cytokines, reduced secretion of anti-inflammatory cytokines, increased expression of surface costimulatory molecules, and increased resistance to serum withdrawal-induced apoptosis. In addition, the pattern of circulating cytokines confirmed activation of proinflammatory cytokines. No modulation of the monocyte phenotype was documented in diabetic control subjects and healthy subjects, thus indicating that the proinflammatory alterations of monocytes are specific and causative of acute Charcot.CONCLUSIONSTogether, these data provide evidence for the role of proinflammatory changes in the immune phenotype of monocytes in the pathogenesis of acute Charcot. These alterations may explain the abnormally intense and prolonged inflammatory response that characterizes this disorder and may represent a potential therapeutic target for specific pharmacological interventions.

Audit of acute Charcot’s disease in the UK: the CDUK study

“…The pathogenesis of Charcot's disease is not known, but it is thought that a subgroup of patients with distal symmetrical neuropathy is at risk and that the condition is triggered in this group by local inflammation [4][5][6]. This inflammation may be caused by minor trauma, surgery, infection or earlier ulceration, and the possibility of a genetic predisposition to abnormal signalling through inflammatory pathways has been suggested [7].…”

Treatment of acute Charcot foot with bisphosphonates: a systematic review of the literature

“…Improvement in the understanding of the underlying pathogenic events provides strong support for an important role of osteoclastic activity and proinflammatory cytokines (including IL-1, IL-6 and TNF-α) in the acute phase of the disease [8,10,11]. The proinflammatory cytokines (including IL-1, IL-6 and TNF-α), by increasing production of RANK-L, play an important role in the activation of osteoclasts [7,24,25]. Moreover, recent studies have emphasised the involvement of the RANK-L/ RANK/OPG axis as certain genetic variants of the OPG (also known as TNFRSF11B) polymorphism may predispose diabetic patients to CNO.…”

An overview of the Charcot foot pathophysiology

“…The activation of RANK stimulates the intracellular pathways that end up by formation of nuclear transcription factor NF-κB. The expression of NF-κB induces osteoclast precursor cells to differentiate into mature osteoclasts (20, 21). Thus, NF-κB pathway is implicated in the excessive osteoclastic activity in diabetic Charcot arthropathy (40, 41) along with its involvement in many conditions that manifest with osteolysis including glucocorticoid-induced osteoporosis, metastatic malignancy, periodontitis, prosthesis-related osteolysis, and rheumatoid arthritis (20, 26).…”