Increased osteoclastic activity in acute Charcot's osteoarthropathy: the role of receptor activator of nuclear factor-kappaB ligand

Diabetologia. 2008 Jun;51(6):1035-40. doi: 10.1007/s00125-008-0992-1. Epub 2008 Apr 4.


Aims/hypothesis: Our aims were to compare osteoclastic activity between patients with acute Charcot's osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG).

Methods: Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices.

Results: In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p=0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p<0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264+/-0.06% to 41.6+/-8.1%, p<0.0001) and diabetic control (0.000+/-0.00% to 14.2+/-16.5%, p<0.0001) patients, and also in healthy control participants (0.004+/-0.01% to 10.5+/-1.9%, p<0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6+/-8.1% to 5.9+/-2.4%, p=0.001), this suppression was not as complete as in diabetic control patients (14.2+/-16.5% to 0.45+/-0.31%, p=0.001) and in healthy control participants (from 10.5+/-1.9% to 0.00+/-0.00%, p<0.0001).

Conclusions/interpretation: These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot's osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthropathy, Neurogenic / physiopathology*
  • Bone Resorption
  • Cell Culture Techniques
  • Diabetes Mellitus, Type 1 / complications*
  • Diabetes Mellitus, Type 2 / complications*
  • Female
  • Humans
  • Macrophage Colony-Stimulating Factor / pharmacology*
  • Male
  • Monocytes / cytology
  • Monocytes / pathology
  • Monocytes / physiology
  • NF-kappa B
  • Osteoclasts / drug effects
  • Osteoclasts / physiology*
  • RANK Ligand / physiology*
  • Receptor Activator of Nuclear Factor-kappa B / physiology


  • NF-kappa B
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • TNFSF11 protein, human
  • Macrophage Colony-Stimulating Factor