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

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

G Mabilleau  1 , N L Petrova, M E Edmonds, A Sabokbar
Affiliations

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

G Mabilleau et al. Diabetologia. 2008 Jun.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Multinucleated TRAcP-positive cells were formed on glass coverslips (a, c, e) capable of lacunar resorption (b, d, f) after 14 and 21 days incubation, respectively, in the presence of 25 ng/ml human M-CSF and 100 ng/ml sRANKL. Newly formed osteoclasts were numerous and highly active in Charcot’s patients (a, b) compared with diabetic (c, d) and healthy control (e, f) participants. Scale bars, 10 μm
Fig. 2
Fig. 2
a Quantitative comparison between the number (n) of TRAcP-positive cells formed in cultures with M-CSF alone (white bars) or with M-CSF and sRANKL (black bars) in patients with Charcot’s osteoarthropathy and diabetic and healthy control participants. b Quantitative comparison between the percentage area resorption in the same cultures and patient groups. Statistical differences between the groups were determined using the Mann–Whitney U test, with significance as follows: a Charcot’s p = 0.059, diabetic control p = 0.003, healthy control p = 0.002; b Charcot’s p < 0.0001, diabetic control p < 0.0001, healthy control p < 0.0001
Fig. 3
Fig. 3
a Comparison between the number (n) of TRAcP-positive cells formed in cultures with M-CSF and sRANKL (black bars) or with M-CSF, sRANKL and excess concentrations of OPG (250 ng/ml) (grey bars) in patients with Charcot’s osteoarthropathy and diabetic and healthy control participants. b Comparison between the percentage area resorption in the same cultures and patient groups. Statistical differences between the groups were determined using the Mann–Whitney U test, with significance as follows: a Charcot’s p = 0.189, diabetic control p = 0.005, healthy control p = 0.003; b Charcot's p = 0.001, diabetic control p = 0.001, healthy control p < 0.0001
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