Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling

Introduction  

Subchondral bone alterations represent an essential component of osteoarthritis (OA). Modifying the abnormal subchondral bone metabolism may be indicated to treat OA. We investigated the effect of diacerein and rhein on the changes occurring in subchondral bone during OA. To this end, we determined the drugs' effects on metalloprotease-13 (MMP-13) synthesis on subchondral bone and on the osteoblast signalling pathways. In osteoclasts, we studied MMP-13 and cathepsin K production as well as cell differentiation, proliferation, and survival.     

Obesity affects the chondrocyte responsiveness to leptin in patients with osteoarthritis

Introduction  

Increasing evidence support the regulatory role of leptin in osteoarthritis (OA). As high circulating concentrations of leptin disrupt the physiological function of the adipokine in obese individuals, the current study has been undertaken to determine whether the elevated levels of leptin found in the joint from obese OA patients also induce changes in the chondrocyte response to leptin.     

Abnormal networks of immune response-related molecules in bone marrow cells from patients with rheumatoid arthritis as revealed by DNA microarray analysis

Introduction  

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic synovitis that progresses to destruction of cartilage and bone. Bone marrow (BM) cells have been shown to contribute to this pathogenesis. In this study, we compared differentially expressed molecules in BM cells from RA and osteoarthritis (OA) patients and analyzed abnormal regulatory networks to identify the role of BM cells in RA.     

Effects of leptin on in vitro maturation, fertilization and embryonic cleavage after ICSI and early developmental expression of leptin (Ob) and leptin receptor (ObR) proteins in the horse

Background  

The identification of the adipocyte-derived obesity gene product, leptin (Ob), and subsequently its association with reproduction in rodents and humans led to speculations that leptin may be involved in the regulation of oocyte and preimplantation embryo development. In mice and pigs, in vitro leptin addition significantly increased meiotic resumption and promoted preimplantation embryo development in a dose-dependent manner. This study was conducted to determine whether leptin supplementation during in vitro maturation (IVM) to horse oocytes could have effects on their developmental capacity after fertilization by IntraCytoplasmic Sperm Injection (ICSI).     

The association between leptin,interleukin-6, and hip radiographic osteoarthritis in older people: a cross-sectional study

Introduction  

The associations between leptin, interleukin (IL)-6, and hip radiographic osteoarthritis (OA) have not been reported, and their roles in obesity-related hip OA are unclear. The aim of this study was to describe the associations between leptin, IL-6, and hip radiographic osteoarthritis (ROA) in older adults.     

Application of <Emphasis Type="Italic">in vivo</Emphasis> micro-computed tomography in the temporal characterisation of subchondral bone architecture in a rat model of low-dose monosodium iodoacetate-induced osteoarthritis

Introduction  

Osteoarthritis (OA) is a complex, multifactorial joint disease affecting both the cartilage and the subchondral bone. Animal models of OA aid in the understanding of the pathogenesis of OA and testing suitable drugs for OA treatment. In this study we characterized the temporal changes in the tibial subchondral bone architecture in a rat model of low-dose monosodium iodoacetate (MIA)-induced OA using in vivo micro-computed tomography (CT).     

Significance of Increased Leptin Expression in Osteoarthritis Patients

Objective

Alterations in leptin expression contributes to the progression of various diseases, including cancers. This meta-analysis investigated the clinical significance of leptin levels in osteoarthritis (OA) patients, with the goal of building a leptin-based diagnostic criterion for OA.

Method

Multiple scientific databases in English and Chinese languages, such as the Cochrane Library Database, CINAHL, Chinese Biomedical (CBM), EMBASE, PubMed, and Web of Science, were exhaustively searched, without any language restrictions, to identify high-quality studies relevant to leptin and OA. Version 12.0 STATA software was used for data analysis. We used odds ratios (OR) and 95% confidence intervals (CI) to test the correlation between serum leptin levels and OA progression.

Results

A total of 11 clinical studies were finally selected for their high quality and relevance to the topic in this meta-analysis. The 11 case-control studies contained a combined total of 3,625 subjects. The meta-analysis results showed that leptin expression was significantly increased in OA patients, compared with the controls (SMD = 0.87, 95%CI: 0.72-1.02, P < 0.001), and there was also a strong association between leptin expression levels and gender (SMD = 8.55, 95%CI: 4.74-12.35, P < 0.001). In ethnicity-stratified subgroup analysis, all the study populations, irrespective of ethnicity, showed remarkably high leptin expression levels in females and in OA patients (all P < 0.05), compared to their respective counterparts.

Conclusion

The present study revealed that increased leptin expression levels are associated with disease severity in OA patients, especially among the female OA patients. Based on our results, we propose that leptin level may be a useful biomarker for the assessment of the clinical status in OA patients.     

The relationship between hand osteoarthritis and serum leptin concentration in participants of the Third National Health and Nutrition Examination Survey

Introduction

Leptin has been suspected to contribute to the development of osteoarthritis (OA). However, this hypothesis has not been tested in large-scale hand OA cohorts. Our study aimed to determine whether there is a cross-sectional relationship between serum leptin levels and hand OA in a population-based sample of US adults.

Method

We used the Third National Health and Nutrition Examination Survey (NHANES III), a national cross-sectional population-based survey, to study the relationship between hand OA and serum leptin concentration. We applied previously established classification criteria for hand OA. Patients with rheumatoid arthritis were excluded. Potential confounders included sex, body mass index, the presence of polyarticular OA, diabetes, and total cholesterol. We estimated unadjusted mean leptin concentration by hand OA status and by all confounders. We further developed a linear regression model to assess mean leptin levels, adjusted for appropriate confounders.

Results

Of 2,477 subjects in the NHANES III sample that had a hand examination and did not have rheumatoid arthritis, 1,056 (42.6%) had a leptin measurement and were included in the analysis. Subjects with and without leptin measurement had similar demographic characteristics. We did not find any significant differences in mean serum leptin levels in subjects with symptomatic hand OA (7.38 ng/ml in males (95% confidence interval (CI) = 5.31, 9.46) and 21.55 ng/ml in females (95% CI = 17.08, 26.02)), asymptomatic hand OA (6.69 ng/ml in males (95% CI = 5.19, 8.18) and 17.09 ng/ml in females (95% CI = 15.00, 19.18)), and no hand OA (8.22 ng/ml in males (95% CI = 7.47, 8.97) and 20.77 ng/ml in females (95% CI = 18.01, 23.53)) in the unadjusted analysis. In a multivariable linear regression model that included variables of hand OA status, age, race/ethnicity, and obesity status, we found no statistically significant association between serum leptin and hand OA status.

Conclusions

In this cross-sectional study of a large representative US cohort, we did not find any evidence to support the hypothesis that serum leptin is associated with hand OA.     

Impact of extracellular matrix derived from osteoarthritis subchondral bone osteoblasts on osteocytes: role of integrinβ1 and focal adhesion kinase signaling cues

Introduction

Our recent study indicated that subchondral bone pathogenesis in osteoarthritis (OA) is associated with osteocyte morphology and phenotypic abnormalities. However, the mechanism underlying this abnormality needs to be identified. In this study we investigated the effect of extracellular matrix (ECM) produced from normal and OA bone on osteocytic cells function.

Methods

De-cellularized matrices, resembling the bone provisional ECM secreted from primary human subchondral bone osteoblasts (SBOs) of normal and OA patients were used as a model to study the effect on osteocytic cells. Osteocytic cells (MLOY4 osteocyte cell line) cultured on normal and OA derived ECMs were analyzed by confocal microscopy, scanning electron microscopy (SEM), cell attachment assays, zymography, apoptosis assays, qRT-PCR and western blotting. The role of integrinβ1 and focal adhesion kinase (FAK) signaling pathways during these interactions were monitored using appropriate blocking antibodies.

Results

The ECM produced by OA SBOs contained less mineral content, showed altered organization of matrix proteins and matrix structure compared with the matrices produced by normal SBOs. Culture of osteocytic cells on these defective OA ECM resulted in a decrease of integrinβ1 expression and the de-activation of FAK cell signaling pathway, which subsequently affected the initial osteocytic cell’s attachment and functions including morphological abnormalities of cytoskeletal structures, focal adhesions, increased apoptosis, altered osteocyte specific gene expression and increased Matrix metalloproteinases (MMP-2) and -9 expression.

Conclusion

This study provides new insights in understanding how altered OA bone matrix can lead to the abnormal osteocyte phenotypic changes, which is typical in OA pathogenesis.     

Chondrogenic differentiation potential of osteoarthritic chondrocytes and their possible use in matrix-associated autologous chondrocyte transplantation

Introduction  

Autologous chondrocyte transplantation (ACT) is a routine technique to regenerate focal cartilage lesions. However, patients with osteoarthritis (OA) are lacking an appropriate long-lasting treatment alternative, partly since it is not known if chondrocytes from OA patients have the same chondrogenic differentiation potential as chondrocytes from donors not affected by OA.     

Whole blood lead levels are associated with radiographic and symptomatic knee osteoarthritis: a cross-sectional analysis in the Johnston County Osteoarthritis Project

Introduction  

Lead (Pb) is known to affect bone, and recent evidence suggests that it has effects on cartilage as well. As osteoarthritis (OA) is a highly prevalent disease affecting bone and cartilage, we undertook the present analysis to determine whether whole blood Pb levels are associated with radiographic and symptomatic OA (rOA and sxOA, respectively) of the knee.     

Hypoxia and vitamin D differently contribute to leptin and dickkopf-related protein 2 production in human osteoarthritic subchondral bone osteoblasts

Introduction

Bone remodelling and increased subchondral densification are important in osteoarthritis (OA). Modifications of bone vascularization parameters, which lead to ischemic episodes associated with hypoxic conditions, have been suspected in OA. Among several factors potentially involved, leptin and dickkopf-related protein 2 (DKK2) are good candidates because they are upregulated in OA osteoblasts (Obs). Therefore, in the present study, we investigated the hypothesis that hypoxia may drive the expression of leptin and DKK2 in OA Obs.

Methods

Obs from the sclerotic portion of OA tibial plateaus were cultured under either 20% or 2% oxygen tension in the presence or not of 50 nM 1,25-dihydroxyvitamin D₃ (VitD₃). The expression of leptin, osteocalcin, DKK2, hypoxia-inducible factor 1α (Hif-1α) and Hif-2α was measured by real-time polymerase chain reaction and leptin production was measured by enzyme-linked immunosorbent assay (ELISA). The expression of Hif-1α, Hif-2α, leptin and DKK2 was reduced using silencing RNAs (siRNAs). The signalling pathway of hypoxia-induced leptin was investigated by Western blot analysis and with mitogen-activated protein kinase (MAPK) inhibitors.

Results

The expression of leptin and DKK2 in Obs was stimulated 7-fold and 1.8-fold, respectively (P <0.05) under hypoxia. Interestingly, whereas VitD₃ stimulated leptin and DKK2 expression 2- and 4.2-fold, respectively, under normoxia, it stimulated their expression by 28- and 6.2-fold, respectively, under hypoxia (P <0.05). The hypoxia-induced leptin production was confirmed by ELISA, particularly in the presence of VitD₃ (P <0.02). Compared to Obs incubated in the presence of scramble siRNAs, siHif-2α inhibited VitD₃-stimulated leptin mRNA and protein levels by 70% (P =0.004) and 60% (P <0.02), respectively, whereas it failed to significantly alter the expression of DKK2. siHif-1α has no effect on these genes. Immunoblot analysis showed that VitD₃ greatly stabilized Hif-2α under hypoxic conditions. The increase in leptin expression under hypoxia was also regulated, by p38 MAPK (P <0.03) and phosphoinositide 3-kinase (P <0.05). We found that the expression of leptin and DKK2 were not related to each other under hypoxia.

Conclusions

Hypoxic conditions via Hif-2 regulation trigger Obs to produce leptin, particularly under VitD₃ stimulation, whereas DKK2 is regulated mainly by VitD₃ rather than hypoxia.     

Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay

Background  

X-linked ocular albinism type 1 (OA1) is caused by mutations in OA1 gene, which encodes a membrane glycoprotein localised to melanosomes. OA1 mainly affects pigment production in the eye, resulting in optic changes associated with albinism including hypopigmentation of the retina, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers and reduced visual acuity. Affected Caucasian males usually appear to have normal skin and hair pigment.     

Dual energy x-ray absorptiometry analysis contributes to the prediction of hip osteoarthritis progression

Introduction  

To determine if structural bone parameters obtained from dual energy X-ray absorptiometry (DXA) contribute to the prediction of progression of hip osteoarthritis (OA) and to test if the difference between the most affected (OA) hip and the contralateral hip adds to this prediction.     

Treatment with ephrin B2 positively impacts the abnormal metabolism of human osteoarthritic chondrocytes

Introduction  

Members of the ephrin system, the ephrin receptor erythropoietin-producing hepatocellular B4 (EphB4) and its specific ligand, ephrin B2, appear to be involved in the bone remodelling process. We recently showed that their interaction inhibits the resorptive activity of human osteoarthritic (OA) subchondral bone osteoblasts. Hence, we further investigated the possible implication of these ephrin members on the catabolic/anabolic activities of human OA chondrocytes.     

Subchondral bone microstructural damage by increased remodelling aggravates experimental osteoarthritis preceded by osteoporosis

Introduction  

Osteoporosis (OP) increases cartilage damage in a combined rabbit model of OP and osteoarthritis (OA). Accordingly, we assessed whether microstructure impairment at subchondral bone aggravates cartilage damage in this experimental model.     

Dietary fatty acid intake affects the risk of developing bone marrow lesions in healthy middle-aged adults without clinical knee osteoarthritis: a prospective cohort study

Introduction  

Fatty acids have been implicated in osteoarthritis (OA), yet the mechanism by which fatty acids affect knee structure and consequently the risk of knee OA has not been fully elucidated. Higher intakes of fatty acids have been shown to be associated with the risk of bone marrow lesions (BMLs) in a healthy population. The aim of this study was to examine the association between fatty acid consumption and the incidence of BMLs in healthy middle-aged adults without clinical knee OA.     

Calcium deposition in osteoarthritic meniscus and meniscal cell culture

Introduction  

Calcium crystals exist in the knee joint fluid of up to 65% of osteoarthritis (OA) patients and the presence of these calcium crystals correlates with the radiographic evidence of hyaline cartilaginous degeneration. This study sought to examine calcium deposition in OA meniscus and to investigate OA meniscal cell-mediated calcium deposition. The hypothesis was that OA meniscal cells may play a role in pathological meniscal calcification.