Activation of β-catenin in Col2-expressing chondrocytes leads to osteoarthritis-like defects in hip joint

Although osteoarthritis (OA) in the hip joint is a common and debilitating degenerative disease, the precise molecular mechanisms underlying its pathological process remains unclear. This study sets out to investigate whether β-catenin plays a critical role in hip OA pathogenesis. Here, we showed overexpressed β-catenin protein in human OA cartilage tissues. Then, we analyzed β-cat(ex3)^Col2ER mice, in which β-catenin gene was conditionally activated in femoral head chondrocytes. At 2 months of age, β-cat(ex3)^Col2ER mice already showed a phenotype of severe cartilage degeneration in the femoral head. More changes observed in β-cat(ex3)^Col2ER mice with age included subchondral sclerosis and osteophyte formation along joint margins, resembling a hip OA phenotype in humans. In addition, cartilage degradation and chondrocyte apoptosis as the results of β-catenin activation possibly contributed to this hip OA-like phenotype. Overall our findings provide direct evidence about the importance of β-catenin in hip OA pathogenesis.     

Understanding the role of chondrocytes in osteoarthritis: utilizing proteomics

Introduction: Proteomic analyses have been acknowledged to carry a significant prospective in elucidating the pathogenesis of several diseases, including osteoarthritis (OA). But it has not been an easy road: major technical issues, mainly derived from the complex and rigid nature of the cartilage tissue, had to be faced; an obstacle that led to the development of different approaches.

Areas covered: In this review, we categorized the proteomic studies undertaken (proteomic analyses of the cartilage, cartilage explants, cultured chondrocytes, and chondrocytes’ secretome) as part of the different strategies developed in order to overcome tissue and disease-specific challenges. Essentially these approaches aimed at identifying differences in the proteome of healthy vs diseased tissue. Our aim was to point out the novel players that have emerged from these analyses and highlight the associated mechanism(s) suggested to play a role in the pathogenesis of OA.

Expert commentary: The identified factors indicate the implication of age-associated mechanisms, such as metabolic deregulation, inflammation, and redox imbalance, in OA onset and/or progression. Taken together these results outline the causal network of the disease and place chondrocytes’ senescence at the center of the emerging aetiopathological atlas.     

Expansion on specific substrates regulates the phenotype and differentiation capacity of human articular chondrocytes

In this study, we investigated if monolayer expansion of adult human articular chondrocytes (AHAC) on specific substrates regulates cell phenotype and post-expansion multilineage differentiation ability. AHAC isolated from cartilage biopsies of five donors were expanded on plastic dishes (PL), on dishes coated with collagen type II (COL), or on slides coated with a ceramic material (Osteologic, OS). The phenotype of expanded chondrocytes was assessed by flow cytometry and real-time RT-PCR. Cells were then cultured in previously established conditions promoting differentiation toward the chondrogenic or osteogenic lineage. AHAC differentiation was assessed histologically, biochemically, and by real-time RT-PCR. As compared to PL-expanded AHAC, those expanded on COL did not exhibit major phenotypic changes, whereas OS-expanded cells expressed (i) higher bone sialoprotein (BSP) (22.6-fold) and lower collagen type II (9.3-fold) mRNA levels, and (ii) lower CD26, CD90 and CD140 surface protein levels (1.4-11.1-fold). Following chondrogenic differentiation, COL-expanded AHAC expressed higher mRNA levels of collagen type II (2.3-fold) and formed tissues with higher glycosaminoglycan (GAG) contents (1.7-fold), whereas OS-expanded cells expressed 16.5-fold lower collagen type II and generated pellets with 2.0-fold lower GAG contents. Following osteogenic differentiation, OS-expanded cells expressed higher levels of BSP (3.9-fold) and collagen type I (2.8-fold) mRNA. In summary, AHAC expansion on COL or OS modulated the de-differentiated cell phenotype and improved the cell differentiation capacity respectively toward the chondrogenic or osteogenic lineage. Phenotypic changes induced by AHAC expansion on specific substrates may mimic pathophysiological events occurring at different stages of osteoarthritis and may be relevant for the engineering of osteochondral tissues.     

Notch signaling is involved in human articular chondrocytes de-differentiation during osteoarthritis

Abstract

Context: During osteoarthritis (OA), chondrocytes undergo de-differentiation, resulting in the acquisition of a fibroblast-like morphology, decreased expression of collagen type II (colII) and aggrecan, and increased expression of collagen type I (colI), metalloproteinase 13 (MMP13) and nitric oxide synthase (eNOS). Notch signaling plays a crucial role during embryogenesis. Several studies showed that Notch is expressed in adulthood. Objective: The aim of our study was to confirm the involvement of Notch signaling in human OA at in vitro and ex vivo levels. Materials and methods: Normal human articular chondrocytes were cultured during four passages either treated or not with a Notch inhibitor: DAPT. Human OA cartilage was cultured with DAPT for five days. Chondrocytes secreted markers and some Notch pathway components were analyzed using Western blotting and qPCR. Results: Passaging chondrocytes induced a decrease in the cartilage markers: colII and aggrecan. DAPT-treated chondrocytes and OA cartilage showed a significant increase in healthy cartilage markers. De-differentiation markers, colI, MMP13 and eNOS, were significantly reduced in DAPT-treated chondrocytes and OA cartilage. Notch1 expression was proportional to colI, MMP13 and eNOS expression and inversely proportional to colII and aggrecan expression in nontreated cultured chondrocytes. Notch ligand: Jagged1 increased in chondrocytes culture. DAPT treatment resulted in reduced Jagged1 expression. Notch target gene HES1 increased during chondrocyte culture and was reduced when treated with DAPT. Conclusion: Targeting Notch signaling during OA might lead to the restitution of the typical chondrocyte phenotype and even to chondrocyte redifferentiation during the pathology.     

A model of temporomandibular joint function in anthropoid primates based on condylar movements during mastication

The hypothesis that the shape of the bony temporomandibular joint (TMJ) is functionally related to sagittal sliding of the condyle during mastication is tested, and a model of the relation of sagittal sliding to mandibular size, TMJ shape, and diet is developed. Sagittal sliding is defined as fore-aft motion of the condyle during mandibular translation and/or angular rotation. Ascending ramus height is used as a structural correlate of the distance between the condyle and the mandibular axis of rotation (CR). Cineradiographic data on sagittal sliding and gape during mastication in Ateles spp., Macaca fascicularis, Papio anubis, and Pan troglodytes in conjunction with comparative data on mandibular size and TMJ shape are used to evaluate the hypothesis. The results show that 1) linear and angular gape are highly positively correlated with sagittal sliding, 2) pure mandibular translation is rare during mastication, 3) the CR is rarely if ever located at the condyle during mastication, 4) angular gape should be standardized in interindividual comparisons of sagittal sliding, and 5) the height of the ascending ramus (and by inference the CR-to-condyle distance) is highly positively correlated with absolute sagittal sliding. Sagittal sliding relative to the length of the articular eminence was the variable used to explore the relation between TMJ shape and sliding. This variable standardized absolute sagittal sliding relative to joint size. The relative depth and orientation of the articular eminence were not correlated with relative sagittal sliding. The anteroposterior curvature of the condyle was highly negatively correlated with relative sagittal sliding. Flat condyles are associated with large amounts of relative sagittal sliding. A flat condyle increases joint contact area, which reduces joint stress. A flat condyle also increases joint congruence, and this may facilitate the combined sliding and rolling motion of the condyle when the sliding motion is relatively large. The shape of the entoglenoid process was also positively correlated with relative sagittal sliding. A relatively large entoglenoid process may help to guide sagittal sliding and prevent excessive mediolateral sliding of the condyle. The functional model makes a number of predictions about the correlations between food consistency and food object size, mandibular size, TMJ shape, and sagittal sliding of the condyle during mastication and incision. Am J Phys Anthropol 109:67–88, 1999. © 1999 Wiley-Liss, Inc.     

Functional role of hedgehog pathway in osteoarthritis

The hedgehog signalling pathway is one of the key regulators of metazoan development, and it plays an important role in the regulation of a variety of developmental and physiological processes. But it is aberrantly activated in many human diseases, including osteoarthritis (OA). In this study, we have reviewed the association of hedgehog signalling pathway in the development and progression of OA and evaluated the efforts to target this pathway for the prevention of OA. Usually in OA, activation of hedgehog induces up-regulation of the expression of hypertrophic markers, including type X collagen, increases production of nitric oxide and prostaglandin E2, several matrix-degrading enzymes including matrix metalloproteinase and a disintegrin and metalloproteinase with thrombospondin motifs in human knee joint cartilage leading to cartilage degeneration, and thus contributes in OA. Targeting hedgehog signalling might be a viable strategy to prevent or treat OA. Chemical inhibitors of hedgehog signalling is promising, but they cause severe side effects. Knockdown of HH gene is not an option for OA treatment in humans because it is not possible to delete HH in larger animals. Efficient knockdown of HH achieved by local delivery of small interfering RNA in future studies utilizing large animal OA models might be a more efficient approach for the prevention of OA. However, it remains a major problem to develop one single scaffold due to the different physiological functions of cartilage and subchondral bones possess. More studies are necessary to identify selective inhibitors for efficiently targeting the hedgehog pathway in clinical conditions.     

Effects of several temporomandibular disorders on the stress distributions of temporomandibular joint: a finite element analysis

The aim of this study was to evaluate stress distributions in the temporomandibular joints (TMJs) with temporomandibular disorders (TMDs) for comparison with healthy TMJs. A model of mandible and normal TMJs was developed according to CT images. The interfaces between the discs and the articular cartilages were treated as contact elements. Nonlinear cable elements were used to simulate disc attachments. Based on this model, seven models of various TMDs were established. The maximum stresses of the discs with anterior, posterior, medial and lateral disc displacement (ADD, PDD, MDD and LDD) were 12.09, 9.33, 10.71 and 6.07 times magnitude of the identically normal disc, respectively. The maximum stresses of the posterior articular eminences in ADD, PDD, MDD, LDD, relaxation of posterior attachments and disc perforation models were 21, 59, 46, 21, 13 and 15 times greater than the normal model, respectively. TMDs could cause increased stresses in the discs and posterior articular eminences.     

Development of the temporomandibular joint in miniature pig embryos

The temporomandibular joint (TMJ) is a synovial joint involved in sliding and hinge movements of lower jaw in mammals. Studies on TMJ development in embryos have been mainly performed using rodents. However, the TMJ structure in rodents differs in several aspects from that in humans. There are few studies on the embryonic development of TMJ in large mammals. In the present study, we investigated the embryonic developmental characteristics of the TMJ in pigs histologically. Embryonic day 35 (E35), E45, E55, E75, E90, and postnatal day 1(P1) embryos/fetuses from the pigs were used for the study. The results showed condensation of mesenchymal cells on E35. The inferior articular cavity was formed on E45, together with a narrow crack in the superior articular cavity region. The superior and inferior articular cavities and articular disc of the TMJ were completely formed on E55. On E75, the condyle showed an obvious conical shape and the superior and inferior joint cavities were enlarged. Furthermore, the mandibular ramus and mandibular body under the neck of the condyle were ossified from E75 to P1 day. The chondrocyte layer of the condyle was significantly thinner from E75 to P1. It is speculated that the spatiotemporal development of the TMJ in miniature pig embryos is similar to that in humans. Embryonic development of the pig TMJ is an important bridge for translating the results of rodent research to medical applications.     

Regulation of MMP-3 expression and secretion by the chemokine eotaxin-1 in human chondrocytes

Background  

Osteoarthritis (OA) is characterized by the degradation of articular cartilage, marked by the breakdown of matrix proteins. Studies demonstrated the involvement of chemokines in this process, and some may potentially serve as diagnostic markers and therapeutic targets; however, the underlying signal transductions are not well understood.     

Growth differentiation factor 5 in cartilage and osteoarthritis: A possible therapeutic candidate

Growth differentiation factor 5 (GDF‐5) is essential for cartilage development and homeostasis. The expression and function of GDF‐5 are highly associated with the pathogenesis of osteoarthritis (OA). OA, characterized by progressive degeneration of joint, particularly in cartilage, causes severe social burden. However, there is no effective approach to reverse the progression of this disease. Over the past decades, extensive studies have demonstrated the protective effects of GDF‐5 against cartilage degeneration and defects. Here, we summarize the current literature describing the role of GDF‐5 in development of cartilage and joints, and the association between the GDF‐5 gene polymorphisms and OA susceptibility. We also shed light on the protective effects of GDF‐5 against OA in terms of direct GDF‐5 supplementation and modulation of the GDF‐5‐related signalling. Finally, we discuss the current limitations in the application of GDF‐5 for the clinical treatment of OA. This review provides a comprehensive insight into the role of GDF‐5 in cartilage and emphasizes GDF‐5 as a potential therapeutic candidate in OA.     

Correlation between MRI evidence of degenerative condylar surface changes, induction of articular disc displacement and pathological joint sounds in the temporomandibular joint

Objectives: The relationship of bony changes in the condylar surfaces in articular disc displacement without reduction in temporomandibular joint (TMJ) was investigated using diagnostic imaging. The study also evaluated whether the bony changes in the condylar surfaces limit disc and condyle motion, and produce pathological joint sounds. Materials and methods: Thirty‐seven joints in 28 patients diagnosed with degenerative bony changes in the condylar surfaces radiographically and anterior disc displacement without reduction using magnetic resonance imaging (MRI) were studied. The bony changes were assessed by radiographic examination and classified into two types: pathological bone changes (PBCs) including erosion, osteophyte formation and deformity, and adaptive bone changes (ABCs) including flattening and concavity. MRI was performed on the TMJ to examine the configuration and position of the discs. Joint sounds in the TMJ were determined using electrovibratograghy with a joint vibration analysis. Results: The articular disc motion to the condyle in the PBC group was smaller than in the ABC group irrespective of the configuration of the disc, even though there were no significant differences between the two types of bony changes in the disc position during jaw closing. The joint vibration analysis of the TMJ showed that joint sounds with a higher frequency were observed in the PBC group than in the ABC group. High energy levels needed to produce the higher frequencies (over 300 Hz) were observed only in the PBC group.     

Oxymatrine exerts protective effects on osteoarthritis via modulating chondrocyte homoeostasis and suppressing osteoclastogenesis

Osteoarthritis (OA) is a common degenerative disease characterized by the progressive destruction both articular cartilage and the subchondral bone. The agents that can effectively suppress chondrocyte degradation and subchondral bone loss are crucial for the prevention and treatment of OA. Oxymatrine (OMT) is a natural compound with anti‐inflammatory and antitumour properties. We found that OMT exhibited a strong inhibitory effect on LPS‐induced chondrocyte inflammation and catabolism. To further support our results, fresh human cartilage explants were treated with LPS to establish an ex vivo degradation model, and the results revealed that OMT inhibited the catabolic events of LPS‐stimulated human cartilage and substantially attenuated the degradation of articular cartilage ex vivo. As subchondral bone remodelling is involved in OA progression, and osteoclasts are a unique cell type in bone resorption, we investigated the effects of OMT on osteoclastogenesis, and the results demonstrated that OMT suppresses RANKL‐induced osteoclastogenesis by suppressing the RANKL‐induced NFATc1 and c‐fos signalling pathway in vitro. Further, we found that the anti‐inflammatory and anti‐osteoclastic effects of oxymatrine are mediated via the inhibition of the NF‐κB and MAPK pathways. In animal studies, OMT suppressed the ACLT‐induced cartilage degradation, and TUNEL assays further confirmed the protective effect of OMT on chondrocyte apoptosis. MicroCT analysis revealed that OMT had an attenuating effect on ACLT‐induced subchondral bone loss in vivo. Taken together, these results show that OMT interferes with the vicious cycle associated with OA and may be a potential therapeutic agent for abnormal subchondral bone loss and cartilage degradation in osteoarthritis.     

Stress relaxation behaviors of articular cartilages in porcine temporomandibular joint

In this study, we tested the compressive stress relaxation behaviors of the mandibular condylar and temporal cartilages in the porcine temporomandibular joint (TMJ). The aim was to determine the quantitative and qualitative similarities and differences of compressive stress relaxation behaviors between the two cartilages. Ten porcine TMJs were used; the articular surface was divided into 5 regions: anterior, central, posterior, lateral and medial. Compressive relaxation test was carried out at a strain level of 5% in each region of the two cartilages. The stress relaxation was monitored over a period of 5 min. In all the regions of the two cartilages, the time-dependent stress relaxation curves showed a marked drop in stress within the initial 10 s, which can be fitted by a standard linear viscoelastic model. The instantaneous moduli in the temporal cartilage were dominantly larger than those in the condylar cartilage, while the condylar cartilage had slightly larger relaxation moduli than the temporal cartilage except for the medial region. The both cartilages showed the regional differences in the compressive stress relaxation behavior, and in the temporal cartilage the lateral and medial regions revealed the largest values for the instantaneous and relaxation moduli. The present results demonstrate that the viscoelastic properties of compressive stress relaxation in both cartilages are region-specific, which might have an important implication for stress distribution and transmission along with the TMJ disc.