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Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XXXVI | Pages 101 - 101
1 Aug 2012
Pearson R Shu K Divyateja H Seagrave M Game F Jeffcoate W Scammell B
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Background

Charcot neuropathic osteoarthropathy is a rare, destructive process affecting the bones and joints of feet in patients with diabetic peripheral neuropathy. The aetiology of Charcot remains unknown, although it has been suggested that it is triggered by the occurrence of inflammation in the foot of a susceptible individual, and that the inflammation results in increased osteoclastic activity.

Hypothesis

The increased bone turnover in acute Charcot is associated with increased concentrations of pro-inflammatory cytokines, related signalling peptides and bone turnover markers.


Orthopaedic Proceedings
Vol. 94-B, Issue SUPP_XVIII | Pages 7 - 7
1 May 2012
Shu K Kendall D Chapman V Barrett D Jeffcoate W Bennett A Scammell B
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Introduction

Both the RANK/RANKL system and the endocannabinoid system have roles in bone remodelling. Activation of CB1 receptors on sympathetic nerve terminals in trabecular bone modulates bone remodelling by attenuating adrenergic inhibition over bone formation. CB2 receptors are involved in the local control of bone cell differentiation and function. Osteoblastic CB2 receptor activation negatively regulates RANKL mRNA expression indicating an interaction between the two systems and that efficient bone remodelling requires a balance between these two systems. The aim of the study was to establish the presence of the different components of the endocannabinoid system and the RANK/RANKL signalling pathway in human bone and osteoclast culture.

Methods

Levels of endocannabinoids (AEA, 2-AG) and their related compounds (OEA, PEA) in human trabecular bone, obtained from patients undergoing elective orthopaedic surgery, were measured using Liquid Chromatography Mass Spectrometry (LC-MS-MS). mRNA for the endocannabinoid synthetic and catabolic enzymes (NAPE-PLD, DAGLa, FAAH, MAGL), cannabinoid-activated receptors (CB1, CB2, PPARs, TRPV1), and RANK, RANKL and NFkB were determined using Taqman Real-Time PCR. Osteoclasts were differentiated from U-937 cells (Human leukaemic monocyte lymphoma cell line), following the sequential treatment using TPA (0.1μg/ml) followed by either TNF-a (3ng/ml) or calcitriol (10−8M), cultured for up to 30 days. Osteoclasts were identified by positive staining with tartrate resistant acid phosphatase (TRAP), multinucleation and the ability to form resorption pits on calcium phosphate coated discs. Taqman Real-Time PCR was performed to detect the expression of the osteoc!

last marker genes TRAP and cathepsin K, together with genes of the endocannabinoid and RANK/RANKL signalling pathways.


Orthopaedic Proceedings
Vol. 93-B, Issue SUPP_III | Pages 311 - 312
1 Jul 2011
Sharma A Seagrave M Fairbairn J Jeffcoate W Scammell B
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Background: The mechanisms underlying the increased prevalence of arterial calcification in diabetes are not understood. An association with distal neuropathy has been reported and a particularly high prevalence was found in patients with Charcot’s disease.

Aim: The aim of this study was to confirm this high prevalence and to determine whether it is specific to that disorder by comparing the results to patients with other types of foot disease.

Methods: A retrospective survey was conducted in three groups of patients with X-rays managed by a specialist service for the diabetic foot between 2002 and 2005. Group A (n=34) comprised patients with an acute Charcot foot, Group B (n=53) included patients with osteomyelitis and Group C (n=35) consisted of patients who had neither osteomyelitis nor Charcot’s disease. All X-rays were independently examined by three observers blinded to the underlying diagnosis, with films from each group being mixed.

Results: No differences existed (p> 0.05) in the mean age of the patients (60, 72 and 68 years, respectively), the proportion of men (68%, 64% and 51%) and the prevalence of nephropathy (41%, 30% and 14%). 100% patients in Group A, 94% in Group B and 80% of Group C had evidence of neuropathy. The overall prevalence of calcification in the three groups was 53%, 66% and 54% (p> 0.05). With all three groups combined, the only factor associated with calcification was disease duration (p=0.004). The prevalence of calcification was higher than the 40% previously reported in patients with neuropathy, but lower than that reported in patients with Charcot.

Conclusion: As there was no difference in the prevalence of calcification between the three groups, it is concluded that the increase is not specific to Charcot’s disease. It is possible that the increase in calcification in each group reflects the effect of local inflammation, possibly by activation of the RANKL/OPG signalling system.