Diabetes-associated Osteoarthritis Research Articles

Study of hydrogen sulfide biosynthesis in synovial tissue from diabetes-associated osteoarthritis and its influence on macrophage phenotype and abundance

Type 2 diabetes (DB) is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Synovial macrophages from OA patients with DB present a marked pro-inflammatory phenotype. Since hydrogen sulphide (H2S) has been previously described to be involved in macrophage polarization, in this study we examined H2S biosynthesis in synovial tissue from OA patients with DB, observing a reduction of H2S-synthetizing enzymes in this subset of individuals. To elucidate these findings, we detected that differentiated TPH-1 cells to macrophages exposed to high levels of glucose presented a lower expression of H2S-synthetizing enzymes and an increased inflammatory response to LPS, showing upregulated expression of markers associated with M1 phenotype (i.e., CD11c, CD86, iNOS, and IL-6) and reduced levels of those related to M2 fate (CD206 and CD163). The co-treatment of the cells with a slow-releasing H2S donor, GYY-4137, attenuated the expression of M1 markers, but failed to modulate the levels of M2 indicators. GYY-4137 also reduced HIF-1α expression and upregulated the protein levels of HO-1, suggesting their involvement in the anti-inflammatory effects of H2S induction. In addition, we observed that intraarticular administration of H2S donor attenuated synovial abundance of CD68+ cells, mainly macrophages, in an in vivo model of OA. Taken together, the findings of this study seem to reinforce the key role of H2S in the M1-like polarization of synovial macrophages associated to OA and specifically its metabolic phenotype, opening new therapeutic perspectives in the management of this pathology.

Clinical features of joint damage in patients with diabetes mellitus

Background. The development of diabetes-associated osteoarthritis is a complex and multifactorial process that depends on the type and compensation of diabetes mellitus (DM). Currently, the data about the role of various risk factors in the development of joint damage among the patients with DM are extremely contradictory. The purpose of the research was to study the clinical characteristics and risk factors of diabetes-associated osteoarthritis in the patients with type 1 DM (T1DM) and type 2DM (T2DM). Materials and methods. 556subjects were examined, who were divided into groups according to the type of DM, the presence, and the degree of severity of diabetes-associated osteoarthritis. Results. In the group of the subjects with T1DM, diabetes-associated osteoarthritis was diagnosed in 185 (74.5%) patients, and in patients with T1DM, joint damage was diagnosed in 241 (78.2%) persons. It was established that in the vast majority of the patients, diabetes-associated osteoarthritis was localized in the joints of the upper limbs. Oligoarthritis was frequent of the patients with T1DM, while polyarthritis is more common in patients with T2DM. It has been established that the probability of diabetes-associated osteoarthritis developing in patients with T1DM probably increases after the age of 35, with a body mass index (BMI) of more than 25.0kg/m2, a level of glycated hemoglobin (HbA1c) of more than 8.0%, and duration of DM of more than 28 years, and in the patients with T1DM, it develops more often among the patients after the age of 61 years, with HbA1c higher than 8.2%, BMI 27.9 kg/m2 and higher, and duration of DM more than 14 years. Conclusions. Measures to prevent diabetes-associated osteoarthritis in patients with DM should be based on long-term compensation of the underlying disease and maintenance of the optimal body mass.

Reduced Levels of H2S in Diabetes-Associated Osteoarthritis Are Linked to Hyperglycaemia, Nrf-2/HO-1 Signalling Downregulation and Chondrocyte Dysfunction.

Different findings indicate that type 2 diabetes is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Changes in the balance of hydrogen sulphide (H2S) are thought to play an important role in the pathogenesis of diabetes and its complications, although its role is still controversial. In this study, we examined the modulation of H2S levels in serum and chondrocytes from OA diabetic (DB) and non-diabetic (non-DB) patients and in cells under glucose stress, in order to elucidate whether impairment in H2S-mediated signalling could participate in the onset of DB-related OA. Here, we identified a reduction in H2S synthesis in the cartilage from OA-DB patients and in cells under glucose stress, which is associated with hyperglycaemia-mediated dysregulation of chondrocyte metabolism. In addition, our results indicate that H2S is an inductor of the Nrf-2/HO-1 signalling pathway in cartilage, but is also a downstream target of Nrf-2 transcriptional activity. Thereby, impairment of the H2S/Nrf-2 axis under glucose stress or DB triggers chondrocyte catabolic responses, favouring the disruption of cartilage homeostasis that characterizes OA pathology. Finally, our findings highlight the benefits of the use of exogeneous sources of H2S in the treatment of DB-OA patients, and warrant future clinical studies.

Clinical features and risk factors of diabetes-associated osteoarthritis

Background. At present, data regarding the role of va­rious risk factors for the development of joint damage in patients with diabetes mellitus (DM) are extremely controversial. Particularly many questions remain regarding the clinical manifestations of this complication, since the development of diabetic arthropathies is a complex and multifaceted process that depends on the type of DM. The purpose of our study was to investigate the clinical features of diabetic arthropathy and to identify plausible risk factors for joint damage in patients with type 1 and 2 DM. Mate­rials and methods. Five hundred and fifty-six patients were divided into groups according to the type of DM, the presence and severity of diabetic arthropathy. Diagnosis of arthropathies was performed ­using the radiographic method and ultrasound of the joints. Results. In the group of patients with type 1 DM, arthropathy was diagnosed in 185 (74.5 %) cases, and in type 2 DM, joint lesions were detected in 241 (78.2 %) individuals. It was found that in the vast majority of patients with DM of both types, arthropathy was localized in the joints of the upper extremities. Most often, small distal or proximal joints of the hand and one of the large joints were involved in the pathological process. Oligoarthritis is characteristic of patients with type 1 DM, whereas polyarthritis is more common in patients with type 2 DM (t = 4.88, p ≤ 0.001). It was found that the risk of developing arthropathy in patients with type 1 DM increases significantly after 35 years, with body mass index (BMI) greater than 25.0 kg/m2, HbA1c levels higher than 8.0 %, and DM duration over 28 years. In patients with type 2 DM, the likelihood of developing arthropathy is increased in patients aged 61 years and older, with HbA1c levels greater than 8.2 %, BMI of 27.9 kg/m2 and above and the duration of diabetes more than 14 years. Conclusions. Preventive measures for diabetic arthropathy should be based on the maintenance of target HbA1c levels of less than 8 % for patients with type 1 DM and 8.2 % for people with type 2 DM, and BMI not higher than 25.0 kg/m2 for individuals with type 1 DM and 27.8 kg/m2 for those with type 2 DM.

Osteoprotegerin as a possible marker of diabetes-associated osteoarthritis

Patients with type 1 diabetes have a higher incidence of osteoarthritis and early manifestation than in the general population. The role of insulin deficiency and hyperglycaemia in the initiation of the destructive process has been proven, but the processes of local and systemic regulation of the balance between anabolic and catabolic processes in the joint and their role in the development of diabetes-associated osteoarthritis remain poorly understood.The aim: to study the role of osteoprotegerin (soluble receptor for tumour necrosis factor - alpha) in the development and progression of diabetes-associated osteoarthritis and its relationship with major metabolic parameters in patients with diabetes mellitus.Materials and methods. 40 patients with type 1 diabetes (17 men and 23 women) were examined, the mean age of the patients was 38.0±2.0 years, the duration of the diabetes was 18.3±1.9 years, the average level of НВА1с was 8.6±0.3 % and 49 patients with type 2 diabetes mellitus (23 men and 26 women), mean age of patients 61.7±1.3 years, duration of diabetes 12.1±1.1 years, mean level HBa1c 7.6±0.1 %. Arthropathy was established in 70.0±7.3 % patients with type 1 diabetes, in 69.4±6.6 % in patients with type 2 diabetes. By sex and type of diabetes, the proportions of patients with and without arthropathy were not statistically different (p> 0.05). The serum content of osteoprotegerin was determined by ELISA using a kit of reagents from Diaclone (France) and enzyme-linked analyser Stat fax 3200 (USA).Results. In patients with arthropathy, a significant increase in osteoprotegerin levels was found. The risk of developing arthropathy in patients with type 1 diabetes with an increased levels of osteoprotegerin is 2.3 times higher than at the normal level (relative risk (RR)=2.33; confidence interval (CI 1.42–3.82; p<0.001), in patients with diabetes 2 type – in 1.55 times (RR=1.55; CI 1.16–1.91). Significant differences in the mean osteoprotegerin level were found for groups absent/present arthropathy. A direct correlation between osteoprotegerin and age was found (p<0.01), diabetes mellitus duration (p <0.05); creatinine level (p<0.05), and an inverse correlation was found with glomerular filtration rate (p<0.05). In the absence of arthropathy, osteoprotegerin and fasting glucose were directly correlated in the type 1 diabetes group (p<0.05). Increased osteoprotegerin levels have been shown to be more common in male patients with longer duration of diabetes. In these patients, no renal lesions were detected, but arthropathy was present as a complication of the underlying disease against the background of an increase in HBA1c.Conclusions. Diabetes-associated osteoarthritis occurs on the background of increased serum osteoprotegerin levels. An increase in the level of osteoprotegerin with an increase in the stage of osteoarthritis was established, so that its level reflects the severity of osteoarthritis. Osteoprotegerin established a direct relationship with the level of creatinine and negatively associated with glomerular filtration rate, i.e. the development and progression of osteoarthritis progression takes place against the background of other vascular complications of diabetes, in particular diabetic nephropathy. An increase in osteoprotegerin is more typical for male patients and depends on the duration of diabetes

Cytokine units of immunoregulation of diabetic-associated osteoarthritis

Joint damage in patients with diabetes mellitus (DM) is a common complication and is associated with the induction of metabolic inflammation against the background of increased catabolic processes in various joint structures. The aim of our study was a study of the levels of proinflammatory cytokines in the serum of patients with diabetes-associated osteoarthritis. Materials and methods. We examined 118 patients, who were divided into groups according to the type of diabetes, the presence and severity of diabetic arthropathy. The content of IL-1α, IL-6, S IL-6-R receptors, TNF-α, osteoprotegerin (soluble TNF-α receptor) in blood serum was determined by enzyme-linked immunosorbent assay. Results Among the examined patients, diabetic arthropathy was diagnosed in more than 70% of patients with diabetes of both types. In patients with diabetic arthropathy, levels of TNF-α (44.5% in type 1 diabetes, 42.9% in type 2 diabetes) and its soluble osteoprotegerin receptor (74.1% in type 1 diabetes) were significantly increased. Type 2 diabetes by 52.9%, as well as IL-6 (with type 1 diabetes by 52.1%, with type 2 diabetes by 64.4%) There is a direct correlation between the severity of joint damage and the level of TNF-α , osteoprotegerin and IL-6. For IL-1, S IL-6-R receptors such changes were not detected.The chances of detecting arthropathy with increasing levels of TNF-a in type 1 diabetes increase by 1.7 (OR = 1, 70 ; DI 1,19-2,44) times, at D 2 type - 1.8 times (OR = 1.78; DI 1.21-1.2.61), with an increase in IL-6 in type 1 diabetes increase by 1.5 (OR = 1.47; DI 1.08 -1.98) times, with type 2 diabetes - 1.3 times (OR = 1.34; DI 1.03-1.74), with elevated levels of osteoprotegerin diabetic arthropathy is 2.3 times more common in patients with type 1 diabetes (OR = 2.33; DI 1.42-3.82) and 1.6 times in patients with type 2 diabetes (SHR = 1.55; DI 1.14-2.10). Conclusions. Thus, TNF-α, osteoprotegerin, and IL-6 may serve as markers of the presence and progression of joint damage in patients with diabetes.

Деякі ревматологічні показники у хворих із діабет-асоційованими остеоартритами

Наразі актуальною є проблема асоціації поширених ревматичних захворювань, таких як ревматоїдний артрит, остеоартроз та остеопороз із цукровим діабетом (ЦД). До теперішнього часу немає єдиного погляду на роль біохімічних та імунних чинників, які викликають ураження суглобів в умовах коморбідності. Метою даного дослідження була оцінка біохімічних ревматологічних показників у хворих на ЦД 1-го та 2-го типів із діабет-асоційованими остеоартритами. Матеріал і методи. У дослідженні взяли участь 105 пацієнтів, яких розподілили на групи за типом діабету, наявністю та ступенем діабетичної артропатії. Пацієнтам проводили діагностику артропатій за допомогою УЗД суглобів і ревмапроби імунотурбодиметричним методом. Результати. У групі пацієнтів із ЦД 1-го типу артропатію виявлено в 64,4% випадків, у групі із ЦД 2-го типу — у 80,0% (t=1,8; p=0,07). У хворих з артропатіями виявлено прямий кореляційний зв’язок стадії артропатії з чинниками «антистрептолізин» (r=0,33; p<0,01), «ревматоїдний чинник» (r=0,26; p<0,05) і «С-реактивний білок» (r=0,43; p<0,001). Встановлено підвищення середнього рівня сечової кислоти зі збільшенням стадії артропатіїяк у групі з ЦД 1-го типу (F=4,4; p=0,009), так і в пацієнтів із ЦД 2-го типу (F=17,9; p<0,001). Висновок. Отримані результати продемонстрували, що як найбільш чутливі діагностичні критерії у хворих із діабет-асоційованими остеоартритами можна рекомендувати використовувати рівень сечової кислоти в крові, ревматоїдного чинника та С-реактивного білка.

Toll-like receptor 4 promotes high glucose-induced catabolic and inflammatory responses in chondrocytes in an NF-κB-dependent manner

Diabetes is an independent risk factor for knee osteoarthritis (OA), and hyperglycaemia-induced inflammation is considered to play an important role in their connection. The Toll-like receptor 4 (TLR4) regulates inflammatory responses in several pathological conditions including diabetes and OA. However, its role in diabetes-associated OA is poorly understood. In this study, we found that TLR4 expression was higher in OA cartilage from patients with type 2 diabetes mellitus (T2DM) than that from non-T2DM patients. Similarly, its expression was induced in primary mouse chondrocytes treated with high glucose, which suggests that TLR4 upregulation in T2DM-associated OA cartilage may originate from hyperglycaemia stimulation. We further discovered that TLR4 promoted high glucose-induced catabolic and inflammatory responses in chondrocytes, and mechanistically, these effects could be explained by the exacerbated activation of the transcription factor nuclear factor kappa B (NF-κB) pathway, since its inhibition by Bay 11-7082 abrogated TLR4 effects on high glucose-treated chondrocytes. Taken together, these findings may reveal a promotive role of TLR4 in regulating hyperglycaemia-induced catabolism and inflammation in T2DM-associated OA, and also implicate that TLR4 inhibition might be of therapeutic significance in treating T2DM-associated OA.

The nuclear factor-erythroid 2-related factor/heme oxygenase-1 axis is critical for the inflammatory features of type 2 diabetes–associated osteoarthritis

Epidemiological findings support the hypothesis that type 2 diabetes mellitus (T2DM) is a risk factor for osteoarthritis (OA). Moreover, OA cartilage from patients with T2DM exhibits a greater response to inflammatory stress, but the molecular mechanism is unclear. To investigate whether the antioxidant defense system participates in this response, we examined here the expression of nuclear factor-erythroid 2-related factor (Nrf-2), a master antioxidant transcription factor, and of heme oxygenase-1 (HO-1), one of its main target genes, in OA cartilage from T2DM and non-T2DM patients as well as in murine chondrocytes exposed to high glucose (HG). Ex vivo experiments indicated that Nrf-2 and HO-1 expression is reduced in T2DM versus non-T2DM OA cartilage (0.57-fold Nrf-2 and 0.34-fold HO-1), and prostaglandin E2 (PGE2) release was increased in samples with low HO-1 expression. HG-exposed, IL-1β-stimulated chondrocytes had lower Nrf-2 levels in vitro, particularly in the nuclear fraction, than chondrocytes exposed to normal glucose (NG). Accordingly, HO-1 levels were also decreased (0.49-fold) in these cells. The HO-1 inducer cobalt protoporphyrin IX more efficiently attenuated PGE2 and IL-6 release in HG+IL-1β-treated cells than in NG+IL-1β-treated cells. Greater reductions in HO-1 expression and increase in PGE2/IL-6 production were observed in HG+IL-1β-stimulated chondrocytes from Nrf-2−/− mice than in chondrocytes from wild-type mice. We conclude that the Nrf-2/HO-1 axis is a critical pathway in the hyperglucidic-mediated dysregulation of chondrocytes. Impairments in this antioxidant system may explain the greater inflammatory responsiveness of OA cartilage from T2DM patients and may inform treatments of such patients.

DIABETES-ASSOCIATED OSTEOARTHRITIS: A SYNTROPY?

This review presents our own and literature data dedicated to predisposing and pathogenetic factors involved in development of a common comorbidity, diabetes-associated osteoarthritis (DAOA). So far, there is no wide-accepted clinical or scientific viewing of DAOA as a distinct clinical phenotype of osteoarthritis (OA). To our knowledge, the role of genetic factors in DAOA development was not discussed in details. Therefore, we have drawn attention to the cross-acting genes involved in both OA and diabetes, i.e., PPARγ, FTO, ADIPOQ, and AGE. These genes encode proteins which can contribute to the pathogenesis of both OA and diabetes. However, some controversies exist about genetic predisposal for OA and diabetes. We review the studies which concern various clinical characteristics of DAOA. We describe a role of chronic hyperglycemia, insulin resistance, advanced glycation end-products (AGE) in development of OA and micro- and macrovascular complications of diabetes. The mechanisms of low-grade inflammation, humoral and cellular immune responses to cartilage antigens, and their role in OA progression are discussed. We underline a similarity of low-grade inflammation in OA and microvascular complications in diabetes. In conclusion, OA and diabetes comorbidity is not a mere coincidence of these diseases. They share some common genetic and pathogenetic factors, a distinct phenotype, and may change thinking of physicians and scientists towards a holistic (personalized) approach to prevention, diagnosis, treatment and prognosis of this comorbidity. We discuss opportunities of DAOA pharmacotherapy based on the key comorbidity feature, i.e., emergence of a new disease property by coexistence of several diseases. One may hypothesize that studying genetic, molecular, and cellular networks in comorbidities may lead to new treatment strategies (‘network pharmacology”) based on targeting the network hubs. We provide examples of such approach in some polypathies (e.g., phenofibrate, a PPARα agonist; simvastatin, a GMGCoA reductase in OA, rheumatoid arthritis and psoriasis), and its potential discuss usefulness is discussed for DAOA. In particular, we provide an example of a pilot study of ademethionine, a methyl group donator.

CLINICAL AND IMMUNOLOGICAL CHARACTERISTICS OF DIABETES-ASSOCIATED OSTEOARTHRITIS

Osteoarthritis (OA) has been shown to be a heterogeneous disease. Diabetes mellitus (DM)associated represents a special OA subtype. Its clinical and immunological characteristics are poorly understood. To assess immune phenotype of the diabetes-associated OA and appropriate relationship between its clinical manifestations and cytokine concentrations in peripheral blood, we examined 78 patients with generalized OA including 52 patients in experimental group (82.6% females) who exhibited clinical manifestations of OA preceded by DM type II for, at least, 1 year, and 26 OA diabetes-free patients (84.6% females). We found that clinical manifestations of DM-associated OA were associated with increased body weight, more pronounced level of joint pains, longer duration of morning stiffness, decreased functionality of hands and large joints, impaired quality of life and more severe clinical pattern of the illness. Pronounced clinical manifestations in OA patients were more typical to the patients who required insulin therapy. The patients with DM type II-associated OA had elevated levels of proinflammatory (IL-6, IL-18) and reduced serum concentrations of anti-infammatory cytokines (IL-10, adiponectin), thus suggesting more pronounced systemic inflammation in patients of the first group. Concentrations of circulating IL-6 correlated with several functional indexes of OA severity. In conclusion, the DM-associated OA represents a special subtype of osteoarthritis, and deserves further studies of its immune pathogenesis and development of new treatment strategies.