Markers of Local Inflammation and Bone Resorption in the Acute Diabetic Charcot Foot

Rasmus Bo Jansen, Tomas Møller Christensen, Jens Bülow, Lene Rørdam, Niklas Rye Jørgensen, Ole Lander Svendsen, Rasmus Bo Jansen, Tomas Møller Christensen, Jens Bülow, Lene Rørdam, Niklas Rye Jørgensen, Ole Lander Svendsen

Abstract

Objective: Due to the localized nature of Charcot foot, systemically altered levels of inflammation markers can be difficult to measure. The aim of this study was to investigate whether it is possible to detect an arteriovenous (A-V) flux in any locally produced inflammatory biomarkers from an acute Charcot foot by comparing local and systemic measurements.

Methods: We included patients with acute diabetic Charcot foot. Blood was sampled from the vena saphena magna on the distal part of the crus bilaterally as well as from the arteria radialis. To minimize the A-V shunting effect, the feet were externally cooled with ice water prior to resampling.

Results: Both before and after cooling, the A-V flux of interleukin-6 (IL-6) between the Charcot feet and the arterial level was significantly higher than the flux between the healthy feet and the arterial level (Δvaluebefore: 7.25 versus 0.41 pg/mL, resp., p = 0.008; Δvalueafter: 10.04 versus 1.68 pg/mL, resp., p = 0.032). There were no differences in the fluxes for other markers of inflammation.

Conclusion: We have found an increased A-V flux of IL-6 in the acute diabetic Charcot foot compared to the healthy foot in the same patients.

Figures

Figure 1
Figure 1
Sites of arterial (red) or venous (blue) blood samples before (tstart) and after (tice) external cooling of the feet. Arterial samples were taken from the a. radialis, or from the a. brachialis if the a. radialis was inaccessible. Venous samples were taken from a large superficial vein at the third distal part of the crus both on the side with a Charcot foot (CF(v)) and on the side without a Charcot foot (non-CF(v)).
Figure 2
Figure 2
Levels of interleukin 6 (IL-6) in arterial and local venous samples in both feet (CF(v) and non-CF(v)) before (tstart) and after (tice) external cooling with ice water. Bars = mean; error bars = SEM.

References

    1. Hartemann-Heurtier A., van G. H., Grimaldi A. The Charcot foot. The Lancet. 2002;360(9347):1776–1779. doi: 10.1016/S0140-6736(02)11671-0.
    1. Fabrin J., Larsen K., Holstein P. E. Long-term follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care. 2000;23(6):796–800. doi: 10.2337/diacare.23.6.796.
    1. Lee L., Blume P. A., Sumpio B. Charcot joint disease in diabetes mellitus. Annals of Vascular Surgery. 2003;17(5):571–580. doi: 10.1007/s10016-003-0039-5.
    1. Rogers L. C., Frykberg R. G. The Charcot foot. The Medical Clinics of North America. 2013;97(5):847–856. doi: 10.1016/j.mcna.2013.04.003.
    1. Grear B. J., Rabinovich A., Brodsky J. W. Charcot arthropathy of the foot and ankle associated with rheumatoid arthritis. Foot & Ankle International. 2013;34(11):1541–1547. doi: 10.1177/1071100713500490.
    1. Munson M. E., Wrobel J. S., Holmes C. M., Hanauer D. A. Data mining for identifying novel associations and temporal relationships with Charcot foot. Journal of Diabetes Research. 2014;2014:13. doi: 10.1155/2014/214353.214353
    1. Bariteau J. T., Tenenbaum S., Rabinovich A., Brodsky J. W. Charcot arthropathy of the foot and ankle in patients with idiopathic neuropathy. Foot & Ankle International. 2014;35(10):996–1001. doi: 10.1177/1071100714543649.
    1. Petrova N. L., Edmonds M. E. Charcot neuro-osteoarthropathy-current standards. Diabetes/Metabolism Research and Reviews. 2008;24(Supplement 1):S58–S61. doi: 10.1002/dmrr.846.
    1. Ward J. D. The diabetic leg. Diabetologia. 1982;22(3):141–147. doi: 10.1007/bf00283741.
    1. Rogers L. C., Frykberg R. G., Armstrong D. G., et al. The Charcot foot in diabetes. Journal of the American Podiatric Medical Association. 2011;101(5):437–446. doi: 10.7547/1010437.
    1. Boulton A. J. M. Diabetic neuropathy and foot complications. Handbook of Clinical Neurology. 2014;126:97–107. doi: 10.1016/B978-0-444-53480-4.00008-4.
    1. Rajbhandari S. M., Jenkins R. C., Davies C., Tesfaye S. Charcot neuroarthropathy in diabetes mellitus. Diabetologia. 2002;45(8):1085–1096. doi: 10.1007/s00125-002-0885-7.
    1. Jeffcoate W. J., Game F., Cavanagh P. R. The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. The Lancet. 2005;366(9502):2058–2061. doi: 10.1016/S0140-6736(05)67029-8.
    1. Jeffcoate W. J. Charcot neuro-osteoarthropathy. Diabetes/Metabolism Research and Reviews. 2008;24(Supplement 1):S62–S65. doi: 10.1002/dmrr.837.
    1. Mabilleau G., Edmonds M. E. Role of neuropathy on fracture healing in Charcot neuro-osteoarthropathy. Journal of Musculoskeletal & Neuronal Interactions. 2010;10(1):84–91.
    1. Chantelau E., Onvlee G. J. Charcot foot in diabetes: farewell to the neurotrophic theory. Hormone and Metabolic Research. 2006;38(6):361–367. doi: 10.1055/s-2006-944525.
    1. Petrova N. L., Dew T. K., Musto R. L., et al. Inflammatory and bone turnover markers in a cross-sectional and prospective study of acute Charcot osteoarthropathy. Diabetic Medicine. 2015;32(2):267–273. doi: 10.1111/dme.12590.
    1. Uccioli L., Sinistro A., Almerighi C., et al. Proinflammatory modulation of the surface and cytokine phenotype of monocytes in patients with acute Charcot foot. Diabetes Care. 2010;33(2):350–355. doi: 10.2337/dc09-1141.
    1. Piaggesi A., Rizzo L., Golia F., et al. Biochemical and ultrasound tests for early diagnosis of active neuro-osteoarthropathy (NOA) of the diabetic foot. Diabetes Research and Clinical Practice. 2002;58(1):1–9. doi: 10.1016/S0168-8227(02)00097-9.
    1. Mabilleau G., Petrova N. L., Edmonds M. E., Sabokbar A. Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand. Diabetologia. 2008;51(6):1035–1040. doi: 10.1007/s00125-008-0992-1.
    1. Gough A., Abraha H., Li F., et al. Measurement of markers of osteoclast and osteoblast activity in patients with acute and chronic diabetic Charcot neuroarthropathy. Diabetic Medicine. 1997;14(7):527–531. doi: 10.1002/(SICI)1096-9136(199707)14:7<527::AID-DIA404>;2-Q.
    1. Ndip A., Williams A., Jude E. B., et al. The RANKL/RANK/OPG signaling pathway mediates medial arterial calcification in diabetic Charcot neuroarthropathy. Diabetes. 2011;60(8):2187–2196. doi: 10.2337/db10-1220.
    1. Pearson R. G., Shu K. S., Divyateja H., et al. Charcot neuropathic osteoarthropathy, pro-inflammatory cytokines and bone turnover markers. Orthopaedic Proceedings. 2012;94-B(Supplement XXXVI):p. 101.
    1. Divyateja H., Shu K. S. S., Pearson R. G., Scammell B. E., Game F. L., Jeffcoate W. J. Local and systemic concentration of pro-inflammatory cytokines, osteoprotegerin, sRANKL and bone turnover markers in acute Charcot foot and in controls. Diabetologia. 2011;54(Supplement 1):S11–S12.
    1. Petrova N. L., Petrov P. K., Edmonds M. E., Shanahan C. M. Novel use of a Dektak 150 surface profiler unmasks differences in resorption pit profiles between control and Charcot patient osteoclasts. Calcified Tissue International. 2014;94(4):403–411. doi: 10.1007/s00223-013-9820-9.
    1. La Fontaine J., Shibuya N., Sampson H. W., Valderrama P. Trabecular quality and cellular characteristics of normal, diabetic, and Charcot bone. The Journal of Foot & Ankle Surgery. 2011;50(6):648–653. doi: 10.1053/j.jfas.2011.05.005.
    1. Folestad A., Ålund M., Asteberg S., et al. IL-17 cytokines in bone healing of diabetic Charcot arthropathy patients: a prospective 2 year follow-up study. Journal of Foot and Ankle Research. 2015;8(1):p. 39. doi: 10.1186/s13047-015-0096-3.
    1. Folestad A., Ålund M., Asteberg S., et al. Role of Wnt/β-catenin and RANKL/OPG in bone healing of diabetic Charcot arthropathy patients. Acta Orthopaedica. 2015;86(4):415–425. doi: 10.3109/17453674.2015.1033606.
    1. Folestad A., Ålund M., Asteberg S., et al. Offloading treatment is linked to activation of proinflammatory cytokines and start of bone repair and remodeling in Charcot arthropathy patients. Journal of Foot and Ankle Research. 2015;8(1):p. 72. doi: 10.1186/s13047-015-0129-y.
    1. Sinha S., Munichoodappa C. S., Kozak G. P. Neuro-arthropathy (Charcot joints) in diabetes mellitus (clinical study of 101 cases) Medicine. 1972;51(3):191–210. doi: 10.1097/00005792-197205000-00006.
    1. Armstrong D. G., Todd W. F., Lavery L. A., Harkless L. B., Bushman T. R. The natural history of acute Charcot’s arthropathy in a diabetic foot specialty clinic. Diabetic Medicine. 1997;14(5):357–363. doi: 10.1002/(SICI)1096-9136(199705)14:5<357::AID-DIA341>;2-8.
    1. Petrova N. L., Shanahan C. M. Neuropathy and the vascular-bone axis in diabetes: lessons from Charcot osteoarthropathy. Osteoporosis International. 2014;25(4):1197–1207. doi: 10.1007/s00198-013-2511-6.
    1. Sattler A. M., Schoppet M., Schaefer J. R., Hofbauer L. C. Novel aspects on RANK ligand and osteoprotegerin in osteoporosis and vascular disease. Calcified Tissue International. 2004;74(1):103–106. doi: 10.1007/s00223-003-0011-y.
    1. Hofbauer L. C., Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292(4):490–495. doi: 10.1001/jama.292.4.490.
    1. Witzke K. A., Vinik A. I., Grant L. M., et al. Loss of RAGE defense: a cause of Charcot neuroarthropathy? Diabetes Care. 2011;34(7):1617–1621. doi: 10.2337/dc10-2315.
    1. Christensen T. M., Simonsen L., Holstein P. E., Svendsen O. L., Bülow J. Sympathetic neuropathy in diabetes mellitus patients does not elicit Charcot osteoarthropathy. Journal of Diabetes and its Complications. 2011;25(5):320–324. doi: 10.1016/j.jdiacomp.2011.06.006.
    1. Guillot M., Vanneuville G., Escande G., Chazal J., Tanguy A. Anatomical study and systematization of veins in the foot. Bulletin de l'Association des anatomistes. 1979;63(183):425–433.
    1. Bergan J. J., Bunke N. The Vein Book. Oxford University Press; 2013.
    1. Kuster G., Lofgren E. P., Hollinshead W. H. Anatomy of the veins of the foot. Surgery, Gynecology & Obstetrics. 1968;127(4):817–823.
    1. Walløe L. Arterio-venous anastomoses in the human skin and their role in temperature control. Temperature. 2016;3(1):92–103. doi: 10.1080/23328940.2015.1088502.
    1. Jansen R. B., Christensen T. M., Bülow J., et al. Bone mineral density and markers of bone turnover and inflammation in diabetes patients with or without a Charcot foot: an 8.5-year prospective case-control study. Journal of Diabetes and its Complications. 2018;32(2):164–170. doi: 10.1016/j.jdiacomp.2017.11.004.
    1. Manolagas S. C. Role of cytokines in bone resorption. Bone. 1995;17(2):S63–S67. doi: 10.1016/8756-3282(95)00180-L.
    1. Nishimura R., Moriyama K., Yasukawa K., Mundy G. R., Yoneda T. Combination of interleukin-6 and soluble interleukin-6 receptors induces differentiation and activation of JAK-STAT and MAP kinase pathways in MG-63 human osteoblastic cells. Journal of Bone and Mineral Research. 1998;13(5):777–785. doi: 10.1359/jbmr.1998.13.5.777.
    1. Yokota K., Sato K., Miyazaki T., et al. Combination of tumor necrosis factor α and interleukin-6 induces mouse osteoclast-like cells with bone resorption activity both in vitro and in vivo. Arthritis & Rheumatology. 2014;66(1):121–129. doi: 10.1002/art.38218.
    1. O’Brien C. A., Gubrij I., Lin S.-C., Saylors R. L., Manolagas S. C. STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-κB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3or parathyroid hormone. Journal of Biological Chemistry. 1999;274(27):19301–19308. doi: 10.1074/jbc.274.27.19301.
    1. Baumhauer J. F., O'Keefe R. J., Schon L. C., Pinzur M. S. Cytokine-induced osteoclastic bone resorption in Charcot arthropathy: an immunohistochemical study. Foot & Ankle International. 2006;27(10):797–800. doi: 10.1177/107110070602701007.
    1. Petrova N. L., Petrov P. K., Edmonds M. E., Shanahan C. M. Inhibition of TNF-α reverses the pathological resorption pit profile of osteoclasts from patients with acute Charcot osteoarthropathy. Journal of Diabetes Research. 2015;2015:10. doi: 10.1155/2015/917945.917945
    1. Nybo M., Poulsen M. K., Grauslund J., Henriksen J. E., Rasmussen L. M. Plasma osteoprotegerin concentrations in peripheral sensory neuropathy in type 1 and type 2 diabetic patients. Diabetic Medicine. 2010;27(3):289–294. doi: 10.1111/j.1464-5491.2010.02940.x.
    1. Yaturu S. Diabetes and skeletal health. Journal of Diabetes. 2009;1(4):246–254. doi: 10.1111/j.1753-0407.2009.00049.x.
    1. Chilelli N. C., Burlina S., Lapolla A. AGEs, rather than hyperglycemia, are responsible for microvascular complications in diabetes: a “glycoxidation-centric” point of view. Nutrition, Metabolism and Cardiovascular Diseases. 2013;23(10):913–919. doi: 10.1016/j.numecd.2013.04.004.
    1. Paul R. G., Bailey A. J. Glycation of collagen: the basis of its central role in the late complications of ageing and diabetes. The International Journal of Biochemistry & Cell Biology. 1996;28(12):1297–1310. doi: 10.1016/S1357-2725(96)00079-9.
    1. Poundarik A. A., Wu P.-C., Evis Z., et al. A direct role of collagen glycation in bone fracture. Journal of the Mechanical Behavior of Biomedical Materials. 2015;52:120–130. doi: 10.1016/j.jmbbm.2015.08.012.
    1. Bierhaus A., Schiekofer S., Schwaninger M., et al. Diabetes-associated sustained activation of the transcription factor nuclear factor-κB. Diabetes. 2001;50(12):2792–2808. doi: 10.2337/diabetes.50.12.2792.
    1. Haslbeck K.-M., Schleicher E., Bierhaus A., et al. The AGE/RAGE/NF-κB pathway may contribute to the pathogenesis of polyneuropathy in impaired glucose tolerance (IGT) Experimental and Clinical Endocrinology & Diabetes. 2005;113(5):288–291. doi: 10.1055/s-2005-865600.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться