The role of genetic factors and monocyte-to-osteoclast differentiation in the pathogenesis of Charcot neuroarthropathy

Kłoska, Anna; Korzon-Burakowska, Anna; Malinowska, Marcelina; Bruhn-Olszewska, Bożena; Gabig-Cimińska, Magdalena; Jakóbkiewicz‐Banecka, Joanna

doi:10.1016/j.diabres.2020.108337

Cited by 12 publications

(11 citation statements)

References 78 publications

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“…This negative result may be due to sample size or that the osseous tissue imbalance begins at a later stage as inflammatory circumstances favoring bone resorption progress or a decreased production of OPG in a neuropathy foot. 1 Notably, the observed lack of increase in levels of bone alkaline phosphatase in response to the raised levels of IL-6 and OPG suggests no difference in osteoblast activity.…”

Section: Discussionmentioning

confidence: 96%

Biomarkers for Early Detection of Charcot Arthropathy: A Prospective Study on Type 2 Diabetes Patients with Severe Neuropathy

Dharmadas,

Kumar,

Pillay

et al. 2023

Foot Ankle Int.

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Background: Charcot arthropathy (CA) is a progressive noninfectious inflammatory disease that causes irreversible destruction to pedal architecture in diabetic neuropathy (DN) patients. The debilitating prognosis demands early detection to prevent the development and progression of this disorder. Dysregulated and persistent production of inflammatory cytokines is reported as the key element in initiating osteoclastogenesis in CA. The study analyzed the potential association of markers of inflammation and bone turnover of prediagnostic serum samples on CA. Methods: Seventy-one type 2 severe DN patients were selected based on inclusion-exclusion criteria. Serum samples of interleukin 6 (IL-6), osteoprotegerin (OPG), bone alkaline phosphatase (BALP), and C-reactive protein (CRP) were analyzed. These patients were followed for the development of symptoms of CA for 12 months. In the year of monitoring, 7 patients developed CA (group 1), whereas the remaining 64 patients did not develop CA (group 2). Results: The rate of development of CA in patients with severe DN was 9.8%. In this group, significantly increased median values of HbA1c (group 2: 8.00 [7.00-9.00], group 1: 10.00 [9.25-11.50], P = .013); IL-6 (group 2: 1.21 [0.72-2.16], group 1: 11.08 [6.65-63.64], P = .008); and CRP (group 2: 1.25 [0.78-3.20], group 1: 3.31 [1.18-41.33], P = .041) were found. The receiver operating characteristic analysis showed that IL-6 was more strongly associated with the onset of CA (IL-6: area under the curve = 0.808; P = .008) than CRP. Cut-off values of ≥6.6 for IL-6 show potential to rule out CA in high-risk patients, with a positive predictive value of 26.1%, a negative predictive value of 97.9%, a sensitivity of 85.7%, and a specificity of 73.4%. Conclusion: In our study population, we found that an exacerbated inflammatory state, reflected by IL-6 values, generally occurred in DN patients before the clinical detection of CA. Level of Evidence: Level II, prospective comparative study.

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Section: Discussionmentioning

confidence: 96%

Biomarkers for Early Detection of Charcot Arthropathy: A Prospective Study on Type 2 Diabetes Patients with Severe Neuropathy

Dharmadas,

Kumar,

Pillay

et al. 2023

Foot Ankle Int.

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“…2 Cardiovascular Department, Shaanxi Provincial People's Hospital, Xi'an 710068, People's Republic of China. 3 School of public health, Xi'an Jiaotong University, Xi'an 710086, People's Republic of China.…”

Section: Authors' Contributionsmentioning

confidence: 99%

“…As diabetes mellitus has become one of the most common disorders now, there will be an increase in the prevalence of DNOAP. Patients with DNOAP often present with joint subluxations, dislocation, or pathological fractures, which reduce the quality of life and increase the mortality signi cantly [2,3] . Accurate diagnosis and appropriate treatment could avoid the delays in patient condition and operation, improve clinical outcomes and lower the medical costs.…”

Section: Introductionmentioning

confidence: 99%

Pathological Characters and Molecular Pathogenesis of Diabetic Neuropathic Osteoarthropathy Cartilages Damage

Liu

Diao²,

Wang

et al. 2021

Preprint

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Background: Diabetic neuropathic osteoarthropathy (DNOAP) is a rare and easily missed complication for diabetes that leads to increased morbidity and mortality. DNOAP is characterized by progressive destruction of bone and joint, but its pathogenesis remains elusive. We herein aimed to investigate the pathological features and pathogenesis of the cartilages damage in DNOAP patients. Methods: The articular cartilages of 8 patients with DNOAP and 8 normal controls were included. Masson staining and safranine O/fixed green staining (S-O) were used to observe the histopathological characteristics of cartilage, and the ultrastructural changes of chondrocytes were detected by electron microscopy. Chondrocyte were isolated from DNOAP group and control group. The expression of RANKL, OPG, IL-1β, IL-6, TNF-α, Aggrecan protein were evaluated by Western blot. ROS levels were measured using a DCFH-DA probe. The percentage of apoptotic cells was determined by flow cytometry. The chondrocytes were cultured with different glucose concentrations to observe the expression of RANKL and OPG.Results: Compared with the control group, the DNOAP group showed fewer chondrocytes, subchondral bone hyperplasia and structural disorder, and a large number of osteoclasts formed in the subchondral bone area. Moreover, mitochondrial and endoplasmic reticulum swelling were observed in the DNOAP chondrocytes. The chromatin was partially broken and concentrated at the edge of nuclear membrane. The ROS fluorescence intensity of chondrocyte in DNOAP group was higher than that in normal control group (28.1 ± 2.3 VS 11.9 ± 0.7, P < 0.05). The expression of RANKL, TNF-α, IL-1β and IL-6 protein in DNOAP group was higher than that in normal control group, while OPG and Aggrecan protein was lower than that in normal control group (both P < 0.05). Flow cytometry showed that the apoptotic rate of chondrocyte in DNOAP group was higher than that in normal control group (P < 0.05). The RANKL/OPG ratio showed significant upward trend when the concentration of glucose was over than 15mM.Conclusions: DNOAP patients tend to have severe destruction of articular cartilage and collapse of organelle structure including mitochondrion and endoplasm reticulum. Indicators of bone metabolism (RANKL, OPG) and inflammatory cytokines (IL-1β, IL-6 and TNF-α) play an important role in promoting the pathogenesis of DNOAP. The glucose concentration higher than 15mM made the RANKL / OPG ratio changed rapidly.

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“…As diabetes mellitus has become one of the most common disorders now, there will be an increase in the prevalence of DNOAP. Patients with DNOAP often present with joint subluxations, dislocation, or pathological fractures, which reduce the quality of life and increase the mortality significantly [ 2 , 3 ]. Accurate diagnosis and appropriate treatment could avoid the delays in patient condition and operation, improve clinical outcomes, and lower the medical costs.…”

Section: Introductionmentioning

confidence: 99%

Cartilage Damage Pathological Characteristics of Diabetic Neuropathic Osteoarthropathy

Liu

Diao

Wang

et al. 2023

Analytical Cellular Pathology

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Background. Diabetic neuropathic osteoarthropathy (DNOAP) is a rare and easily missed complication for diabetes that leads to increased morbidity and mortality. DNOAP is characterized by progressive destruction of bone and joint, but its pathogenesis remains elusive. We herein aimed to investigate the pathological features and pathogenesis of the cartilages damage in DNOAP patients. Methods. The articular cartilages of eight patients with DNOAP and eight normal controls were included. Masson staining and safranine O/fixed green staining (S-O) were used to observe the histopathological characteristics of cartilage. The ultrastructure and morphology of chondrocytes were detected by electron microscopy and toluidine blue staining. Chondrocytes were isolated from DNOAP group and control group. The expression of receptor activator of nuclear factor kappaB ligand (RANKL), osteoprotegerin (OPG), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and Aggrecan protein was evaluated by western blot. Reactive oxygen species (ROS) levels were measured using a 2′,7′-dichlorofluorescin diacetate (DCFH-DA) probe. The percentage of apoptotic cells was determined by flow cytometry (FCM). The chondrocytes were cultured with different glucose concentrations to observe the expression of RANKL and OPG. Results. Compared with the control group, the DNOAP group showed fewer chondrocytes, subchondral bone hyperplasia, and structural disorder, and a large number of osteoclasts formed in the subchondral bone area. Moreover, mitochondrial and endoplasmic reticulum swellings were observed in the DNOAP chondrocytes. The chromatin was partially broken and concentrated at the edge of nuclear membrane. The ROS fluorescence intensity of chondrocyte in DNOAP group was higher than that in normal control group ( 28.1 ± 2.3 vs. 11.9 ± 0.7 ; P < 0.05 ). The expression of RANKL, TNF-α, IL-1β, and IL-6 protein in DNOAP group was higher than that in normal control group, whereas OPG and Aggrecan protein were lower than that in normal control group (both P < 0.05 ). FCM showed that the apoptotic rate of chondrocyte in DNOAP group was higher than that in normal control group ( P < 0.05 ). The RANKL/OPG ratio showed significant upward trend when the concentration of glucose was over than 15 mM. Conclusions. DNOAP patients tend to have severe destruction of articular cartilage and collapse of organelle structure including mitochondrion and endoplasm reticulum. Indicators of bone metabolism (RANKL and OPG) and inflammatory cytokines (IL-1β, IL-6, and TNF-α) play an important role in promoting the pathogenesis of DNOAP. The glucose concentration higher than 15 mM made the RANKL/OPG ratio change rapidly.

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The role of genetic factors and monocyte-to-osteoclast differentiation in the pathogenesis of Charcot neuroarthropathy

Cited by 12 publications

References 78 publications

Biomarkers for Early Detection of Charcot Arthropathy: A Prospective Study on Type 2 Diabetes Patients with Severe Neuropathy

Biomarkers for Early Detection of Charcot Arthropathy: A Prospective Study on Type 2 Diabetes Patients with Severe Neuropathy

Pathological Characters and Molecular Pathogenesis of Diabetic Neuropathic Osteoarthropathy Cartilages Damage

Cartilage Damage Pathological Characteristics of Diabetic Neuropathic Osteoarthropathy

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