Subchondral Bone Sclerosis Research Articles

Cellular and molecular mechanisms of subchondral bone sclerosis in hip osteoarthritis: the potential roles of multipotential stromal cells and osteocytes

Cellular and molecular mechanisms of subchondral bone sclerosis in hip osteoarthritis: the potential roles of multipotential stromal cells and osteocytes

Comparison of secretome from osteoblasts derived from sclerotic versus non-sclerotic subchondral bone in OA: A pilot study.

ObjectiveOsteoarthritis (OA) is characterized by cartilage degradation but also by other joint tissues modifications like subchondral bone sclerosis. In this study, we used a proteomic approach to compare secretome of osteoblast isolated from sclerotic (SC) or non sclerotic (NSC) area of OA subchondral bone.DesignSecretome was analyzed using differential quantitative and relative label free analysis on nanoUPLC G2 HDMS system. mRNA of the more differentially secreted proteins were quantified by RT-PCR in cell culture from 5 other patients. Finally, osteomodulin and fibulin-3 sequences were quantified by western blot and immunoassays in serum and culture supernatants.Results175 proteins were identified in NSC osteoblast secretome. Data are available via ProteomeXchange with identifier PXD008494. Compared to NSC osteoblast secretome, 12 proteins were significantly less secreted (Osteomodulin, IGFBP5, VCAM-1, IGF2, 78 kDa glucose-regulated protein, versican, calumenin, IGFBP2, thrombospondin-4, periostin, reticulocalbin 1 and osteonectin), and 13 proteins were significantly more secreted by SC osteoblasts (CHI3L1, fibulin-3, SERPINE2, IGFBP6, SH3BGRL3, SERPINE1, reticulocalbin3, alpha-2-HS-glycoprotein, TIMP-2, IGFBP3, TIMP-1, SERPINF1, CSF-1). Similar changes in osteomodulin, IGF2, SERPINE1, fibulin-3 and CHI3L1 mRNA levels were observed. ELISAs assays confirm the decrease by half of osteomodulin protein in SC osteoblasts supernatant compared to NSC and in OA patients serum compared to healthy subjects. Fibulin-3 epitopes Fib3-1, Fib3-2 and Fib3-3 were also increased in SC osteoblasts supernatant compared to NSC.ConclusionsWe highlighted some proteins differentially secreted by the osteoblasts coming from OA subchondral bone sclerosis. These changes contribute to explain some features observed in OA subchondral bone, like the increase of bone remodeling or abnormalities in bone matrix mineralization. Among identified proteins, osteomodulin was found decreased and fibulin-3 increased in serum of OA patients. These findings suggest that osteomodulin and fibulin-3 fragments could be biomarkers to monitor early changes in subchondral bone metabolism in OA.

Development and characterization of various osteoarthritis models for tissue engineering.

Osteoarthritis (OA) is characterized by a progressive loss of articular cartilage, subchondral bone sclerosis and synovial inflammation and is the most common chronic condition worldwide today. However, most treatments have focused on pain relief and OA symptoms. For these reasons, many ongoing studies are currently trying to develop efficient and successful therapies based on its pathology. Animal models that mimic the histopathology and symptoms of OA have a critical role in OA research and make it possible to investigate both secondary osteoarthritic changes due to a precedent event such as traumatic injury and naturally occurring changes for the development of therapeutics which can be tested in preclinical and clinical OA trials. We induced OA in various animal models including rats, rabbits and guinea pigs by chemical, surgical and naturally occurring methods. In particular, the Dunkin-Hartley guinea pig is very attractive as an OA animal model because OA slowly progresses which is similar to human primary OA. Thus, this animal model mimics the pathophysiological process and environment of human primary OA. Besides the spontaneous OA model, anterior cruciate ligament transection (ACLT) with medial meniscectomy and bilateral ovariectomy (OVX) as well as a chemical technique using sodium monoiodoacetate (MIA) were used to induce OA. We found that ACLT in the rat model induced OA changes in the histology and micro-CT image compared to OVX. The osteoarthritic change significantly increased following ACLT surgery in the rabbit model. Furthermore, we identified that OA pathogenic changes occurred in a time-dependent manner in spontaneous Dunkin-Hartley guinea pigs. The MIA injection model is a rapid and minimally invasive method for inducing OA in animal models, whereas the spontaneous OA model has a slow and gradual progression of OA similar to human primary OA. We observed that histological OA change was extraordinarily increased at 9 ½ months in the spontaneous OA model, and thus, the grade was similar with that of the MIA model. Therefore, this study reports on OA pathology using various animal models as well as the spontaneous results naturally occurring in an OA animal model which had developed cartilage lesions and progressive osteoarthritic changes.

Knocking out or pharmaceutical inhibition of fatty acid binding protein 4 (FABP4) alleviates osteoarthritis induced by high-fat diet in mice

Adipokines play roles in the pathogenesis of osteoarthritis (OA). Fatty acid binding protein 4 (FABP4) is a novel adipokine that is closely associated with obesity and metabolic diseases. The aim of this study was to discover the potential role of FABP4 in OA. Seventy-two FABP4 knockout mice (KO) in C57BL/6N background and wild-type littermates (WT) (male, 6-week-old) were fed with a high-fat diet (HFD, 60% calorie) or standard diet (STD, 11.6% calorie) for 3 months, 6 months and 9 months (n=6 each). In the parallel study, forty-eight 6-week-old male WT mice were fed with HFD or STD, and simultaneously treated with daily oral gavage of selective FABP4 inhibitor BMS309403 (15mg/kg/d) or vehicle for 4 months and 6 months (n=6 each). Serum FABP4 and cartilage oligomeric matrix protein (COMP) concentration was quantified. Histological assessment of knee OA and micro-CT analysis of subchondral bone were performed. HFD induced obesity in mice. After 3 months and 6 months of HFD, KO mice showed alleviated cartilage degradation and synovitis, with significantly lower COMP, modified Mankin OA score, and MMP-13/ADAMTS4 expression. After 6 months and 9 months of HFD, KO mice showed less osteophyte formation and subchondral bone sclerosis. Chronic treatment of BMS309403 for 4 months and 6 months significantly alleviated cartilage degradation, but had no effects on the subchondral bone. Knocking out or pharmaceutical inhibition of FABP4 did not have significant effects on lean mice fed with STD. Knocking out or pharmaceutical inhibition of FABP4 alleviates OA induced by HFD in mice.

Cartilage MicroRNA Dysregulation During the Onset and Progression of Mouse Osteoarthritis Is Independent of Aggrecanolysis and Overlaps With Candidates From End-Stage Human Disease.

To identify candidate microRNAs (miRNAs) that potentially regulate the initiation and progression of osteoarthritis (OA). OA was induced in 10-12-week-old male wild-type C57BL/6 mice and in mice resistant to aggrecanase cleavage (Acan p.374ALGS→374NVYS) by destabilization of the medial meniscus (DMM). Pathologic changes of OA were scored histologically. RNA from cartilage and subchondral bone was harvested in parallel by laser microdissection at 1 week and 6 weeks postsurgery. Global miRNA expression profiling was performed using Agilent microarrays and was validated by quantitative polymerase chain reaction analysis. Wild-type DMM mice had characteristic cartilage degeneration, subchondral bone sclerosis, and osteophyte formation. While no miRNA dysregulation was seen in subchondral bone, 139 miRNAs were differentially expressed in cartilage obtained at 1 and/or 6 weeks after OA initiation from wild-type mice that underwent DMM. To prioritize OA candidates, dysregulated miRNAs with human orthologs were filtered, and paired miRNA/messenger RNA (mRNA) expression analysis was conducted to identify those with corresponding changes in mRNA target transcripts in the DMM mouse cartilage. An important cohort also overlapped with miRNAs identified in human end-stage OA. Comparisons of miRNA dysregulation in DMM mouse cartilage where aggrecan cleavage was genetically ablated demonstrated that all candidates were independent of aggrecan breakdown, earmarking these as important to the critical stages of OA initiation. Furthermore, functional enrichment analysis and data annotation revealed the responses to mechanical stimuli, apoptotic processes, and core extracellular matrix structural and regulatory factors to be potentially influenced by OA-dysregulated miRNA/mRNA networks. Our comprehensive analyses identified high-priority miRNA candidates that have potential as biomarkers and therapeutic targets in human OA.

Alterations of Subchondral Bone Progenitor Cells in Human Knee and Hip Osteoarthritis Lead to a Bone Sclerosis Phenotype.

Subchondral bone tissue plays a key role in the initiation and progression of human and experimental osteoarthritis and has received considerable interest as a treatment target. Elevated bone turnover and remodeling leads to subchondral bone sclerosis that is characterized by an increase in bone material that is less mineralized. The aim of this study was to investigate whether perturbations in subchondral bone-resident progenitor cells might play a role in aberrant bone formation in osteoarthritis. Colony formation assays indicated similar clonogenicity of progenitor cells from non-sclerotic and sclerotic subchondral trabecular bone tissues of osteoarthritic knee and hip joints compared with controls from iliac crest bone. However, the osteogenic potential at the clonal level was approximately two-fold higher in osteoarthritis than controls. An osteogenic differentiation assay indicated an efficient induction of alkaline phosphatase activity but blunted in vitro matrix mineralization irrespective of the presence of sclerosis. Micro-computed tomography and histology demonstrated the formation of de novo calcified tissues by osteoblast-like cells in an ectopic implantation model. The expression of bone sialoprotein, a marker for osteoblast maturation and mineralization, was significantly less in sclerotic progenitor cells. Perturbation of resident progenitor cell function is associated with subchondral bone sclerosis and may be a treatment target for osteoarthritis.

Osteochondritis dissecans-like lesions of the occipital condyle and cervical articular process joints in a Saddlebred colt horse

BackgroundOsteochondritis dissecans (OCD) is a sequela to osteochondrosis, whereby the cartilage superficial to the site of osteochondrosis fractures and gives rise to osteochondral fragments in the affected joint. In this case, both the radiological and computed tomography findings were supportive of classical severe OCD but the histologic findings were not supportive of the diagnosis of OCD.Case presentationA 1 year and 6 months old, Saddlebred, colt was presented for evaluation of chronic cervical pain. Standing laterolateral radiographs revealed an osteochondral fragment with corresponding irregular subchondral bone defect at one of the occipital condyle. Computed tomography confirmed the presence of osteochondral fragments at the left occipital condyle and several articular process joints of the cervical spine, with associated subchondral bone defects and sclerosis, suggestive of OCD. However, the lack of ischemic chondronecrosis microscopically was not supportive of a histologic diagnosis of OCD. Therefore, the term ‘OCD-like lesions’ was deemed most appropriate for these cervical lesions.ConclusionIn the event where imaging features were characteristics of OCD but lack of histologic evidence of ischemic chondronecrosis, the term ‘OCD-like lesion’ is deemed most appropriate.

Contrast enhanced μCT imaging of early articular changes in a pre-clinical model of osteoarthritis.

The objective of this study was to characterize early osteoarthritis (OA) development in cartilage and bone tissues in the rat medial meniscus transection (MMT) model using non-destructive equilibrium partitioning of an ionic contrast agent micro-computed tomography (EPIC-μCT) imaging. Cartilage fibrillation, one of the first physiological developments in OA, was quantified in the rat tibial plateau as three-dimensional (3D) cartilage surface roughness using a custom surface-rendering algorithm. Male Lewis rats underwent MMT or sham-operation in the left leg. At 1- and 3-weeks post-surgery, the animals (n=7-8 per group) were euthanized and the left legs were scanned using EPIC-μCT imaging to quantify cartilage and bone parameters. In addition, a custom algorithm was developed to measure the roughness of 3D surfaces. This algorithm was validated and used to quantify cartilage surface roughness changes as a function of time post-surgery. MMT surgery resulted in significantly greater cartilage damage and subchondral bone sclerosis with the damage increasing in both severity and area from 1- to 3-weeks post-surgery. Analysis of rendered 3D surfaces could accurately distinguish early changes in joints developing OA, detecting significant increases of 45% and 124% in surface roughness at 1- and 3-weeks post-surgery respectively. Disease progression in the MMT model progresses sequentially through changes in the cartilage articular surface, extracellular matrix composition, and then osteophyte mineralization and subchondral bone sclerosis. Cartilage surface roughness is a quantitative, early indicator of degenerative joint disease in small animal OA models and can potentially be used to evaluate therapeutic strategies.

Alteration of Wnt5a expression and of the non-canonical Wnt/PCP and Wnt/PKC-Ca2+ pathways in human osteoarthritis osteoblasts.

ObjectiveClinical and in vitro studies suggest that subchondral bone sclerosis due to abnormal osteoblasts (Ob) is involved in the progression and/or onset of osteoarthritis (OA). Human Ob isolated from sclerotic subchondral OA bone tissue show an altered phenotype, a decreased canonical Wnt/β-catenin signaling pathway (cWnt), and a reduced mineralization in vitro. In addition to the cWnt pathway, at least two non-canonical signaling pathways, the Wnt/PKC and Wnt/PCP pathway have been described. However, there are no reports of either pathway in OA Ob. Here, we studied the two non-canonical pathways in OA Ob and if they influence their phenotype.MethodsHuman primary subchondral Ob were isolated from the subchondral bone plate of tibial plateaus of OA patients undergoing total knee arthroplasty, or of normal individuals at autopsy. The expression of genes involved in non-canonical Wnt signaling was evaluated by qRT-PCR and their protein production by Western blot analysis. Alkaline phosphatase activity and osteocalcin secretion (OC) were determined with substrate hydrolysis and EIA, respectively. Mineralization levels were evaluated with Alizarin Red Staining, Wnt/PKC and Wnt/PCP pathways by target gene expression and their respective activity using the NFAT and AP-1 luciferase reporter assays.ResultsOA Ob showed an altered phenotype as illustrated by an increased alkaline phosphatase activity and osteocalcin release compared to normal Ob. The expression of the non-canonical Wnt5a ligand was increased in OA Ob compared to normal. Whereas, the expression of LGR5 was significantly increased in OA Ob compared to normal Ob, the expression of LGR4 was similar. Wnt5a directly stimulated the expression and production of LGR5, contrasting, Wnt5a did not stimulate the expression of LGR4. Wnt5a also stimulated the phosphorylation of both JNK and PKC, as well as the activity of both NFAT and AP-1 transcription factors. The inhibition of Wnt5a expression partially corrects the abnormal mineralization, OC secretion and ALPase activity of OA Ob.ConclusionThese data indicate that the alteration of Wnt5a, a non-canonical Wnt signaling activator, is implicated in the modified signalisation and phenotype observed in OA Ob.

Cryptotanshinone protects against IL-1β-induced inflammation in human osteoarthritis chondrocytes and ameliorates the progression of osteoarthritis in mice

Osteoarthritis (OA) is a common degenerative disease characterized by progressive erosion of articular cartilage, subchondral bone sclerosis and synovitis. Cryptotanshinone (CTS), an active component extracted from the root of Salvia miltiorrhiza Bunge, has been shown to have potent anti-inflammatory effects. However, its effects on OA have not been clearly elucidated. This study aimed to assess the effect of CTS on human OA chondrocytes and mice OA models. Human OA chondrocytes were pretreated with CTS (5, 10 and 20μM) for 2h and subsequently stimulated with IL-1β for 24h. Production of NO, PGE2, IL-6, TNF-α was evaluated by the Griess reaction and ELISA. The protein expression of COX-2, iNOs, MMP-3, MMP13, COX-2, ADAMTS-5, JNK, p-JNK, ERK, p-ERK, p38, p-p38, p-IKKα/β, p65, p-p65, IκB-α, and p-IκB-α was tested by Western blot. In vivo, the severity of OA was determined by histological analysis. We found that CTS significantly inhibited the IL-1β-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-3, MMP-13, and ADAMTS-5. Furthermore, CTS in dramatically suppressed IL-1β-stimulated NF-κB and MAPK activation. Immunofluorescence staining demonstrated that CTS could suppress IL-1β-induced phosphorylation of p65 nuclear translocation. In vivo, treatment of CTS prevented the destruction of cartilage and the thickening of subchondral bone in mice OA models. These results indicate that the therapeutic effect of CTS on OA is accomplished through the inhibition of both NF-κB and MAPK signaling pathways. Our findings provide the evidence to develop CTS as a potential therapeutic agent f or patients with OA.

Activated FGFR3 prevents subchondral bone sclerosis during the development of osteoarthritis in transgenic mice with achondroplasia.

The purpose of this study is to investigate the morphometric changes of the subchondral bone during the development of osteoarthritis (OA) in transgenic mice with achondroplasia (Fgfr3ach ) carrying a heterozygous gain-of-function mutation in Fgfr3. Two OA models (spontaneously developed with age: The aging model, and surgically induced by destabilization of the medial meniscus: The DMM model) were established. Articular cartilage, epiphysis, and metaphysis of the knee joint were histologically and morphometrically compared between wild-type mice, and Fgfr3ach mice in both OA models. Articular cartilage degeneration was scored according to the Osteoarthritis Research Society International (OARSI) scoring system. Several morphometric parameters including bone mineral density (BMD), bone volume/tissue volume (BV/TV), trabecular bone thickness (Tb.Th), and subchondral bone thickness in the medial tibial plateau (MTP) (Sb.Th med) were quantified by micro-computed tomography (CT). In the aging model, although there were no significant differences in the OARSI score between wild-type mice and Fgfr3ach mice, Sb.Th med and Tb.Th in the epiphysis significantly increased in wild-type mice. In the DMM model, the OARSI score of the medial compartment was significantly lower in Fgfr3ach mice than in wild-type mice. BMD, BV/TV, and Tb.Th in the epiphysis increased in wild-type mice and unchanged in Fgfr3ach mice, and the Sb.Th med was significantly larger in wild-type mice after surgery. Subchondral sclerosis, which preceded the cartilage degeneration, was inhibited in Fgfr3ach mice. Activated FGFR3 signaling prevented sclerotic changes of the subchondral bone and subsequent cartilage degeneration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:300-308, 2018.

A Dual Role of Upper Zone of Growth Plate and Cartilage Matrix-Associated Protein in Human and Mouse Osteoarthritic Cartilage: Inhibition of Aggrecanases and Promotion of Bone Turnover.

Cartilage damage and subchondral bone changes are closely connected in osteoarthritis. Nevertheless, how these processes are interlinked is, to date, incompletely understood. This study was undertaken to investigate the mechanistic role of a cartilage-derived protein, upper zone of growth plate and cartilage matrix-associated protein (UCMA), in osteoarthritis-related cartilage and bone changes. UCMA expression was assessed in healthy and osteoarthritic human and mouse cartilage. For analysis of cartilage and bone changes, osteoarthritis was induced by destabilization of the medial meniscus (DMM) in wild-type (WT) and Ucma-deficient mice. UCMA-collagen interactions, the effect of UCMA on aggrecanase activity, and the impact of recombinant UCMA on osteoclast differentiation were studied in vitro. UCMA was found to be overexpressed in human and mouse osteoarthritic cartilage. DMM-triggered cartilage changes, including increased structural damage, proteoglycan loss, and chondrocyte cell death, were aggravated in Ucma-deficient mice compared to WT littermates, thereby demonstrating the potential chondroprotective effects of UCMA. Moreover, UCMA inhibited ADAMTS-dependent aggrecanase activity and directly interacted with cartilage-specific collagen types. In contrast, osteoarthritis-related bone changes were significantly reduced in Ucma-deficient mice, showing less pronounced osteophyte formation and subchondral bone sclerosis. Mechanistically, UCMA directly promoted osteoclast differentiation in vitro. UCMA appears to link cartilage with bone changes in osteoarthritis by supporting cartilage integrity as an endogenous inhibitor of aggrecanases while also promoting osteoclastogenesis and subchondral bone turnover. Thus, UCMA represents an important link between cartilage and bone in osteoarthritis.

Cartilage lesions in feline stifle joints – Associations with articular mineralizations and implications for osteoarthritis

Feline stifle osteoarthritis (OA) is common, however little is known about the early stages of the disease. Furthermore, the importance of small articular mineralizations (AMs) in feline stifle OA is controversial. This study aimed to describe microscopic articular cartilage lesions and to investigate associations between cartilage lesions and AMs, synovitis, osteochondral junction findings and subchondral bone sclerosis. Stifles of 29 cats, aged 1–23years and euthanized for reasons other than stifle disease, were examined. Osteochondral tissue and synovial membrane changes were histologically evaluated. Computed tomography and radiography were used for evaluation of AMs. Global cartilage scores (GCS, n=28) were summarized and joints assigned a histologic OA grade. Minimal to mild histologic OA was seen in 24/28 joints. In 27/29 joints tibial cartilage lesions were seen, whereas femoral lesions were only seen in two joints. Articular mineralizations were detected in 13/29 joints, 11 were small and 12 were located entirely within the medial meniscus. There was no association between GCS and presence or volumes of AMs. However, higher GCS was associated with synovitis (P=0.001) and age (P<0.0005). Presence of subchondral bone sclerosis (P<0.0005) and disruption of the calcified cartilage or tidemark (P<0.0005) were associated with cartilage lesions. We conclude that the tibial articular cartilage is a common location for histologic OA lesions in cats. Synovitis and changes in the subchondral bone and calcified cartilage may be important in the pathogenesis of feline stifle OA, whereas small AMs likely represent incidental findings.

Automated assessment of bone changes in cross-sectional micro-CT studies of murine experimental osteoarthritis.

ObjectiveThe degradation of articular cartilage, which characterises osteoarthritis (OA), is usually paired with excessive bone remodelling, including subchondral bone sclerosis, cysts, and osteophyte formation. Experimental models of OA are widely used to investigate pathogenesis, yet few validated methodologies for assessing periarticular bone morphology exist and quantitative measurements are limited by manual segmentation of micro-CT scans. The aim of this work was to chart the temporal changes in periarticular bone in murine OA by novel, automated micro-CT methods.MethodsOA was induced by destabilisation of the medial meniscus (DMM) in 10-week old male mice and disease assessed cross-sectionally from 1- to 20-weeks post-surgery. A novel approach was developed to automatically segment subchondral bone compartments into plate and trabecular bone in micro-CT scans of tibial epiphyses. Osteophyte volume, as assessed by shape differences using 3D image registration, and by measuring total epiphyseal volume was performed.ResultsSignificant linear and volumetric structural modifications in subchondral bone compartments and osteophytes were measured from 4-weeks post-surgery and showed progressive changes at all time points; by 20 weeks, medial subchondral bone plate thickness increased by 160±19.5 μm and the medial osteophyte grew by 0.124±0.028 μm3. Excellent agreement was found when automated measurements were compared with manual assessments.ConclusionOur automated methods for assessing bone changes in murine periarticular bone are rapid, quantitative, and highly accurate, and promise to be a useful tool in future preclinical studies of OA progression and treatment. The current approaches were developed specifically for cross-sectional micro-CT studies but could be applied to longitudinal studies.

Correlation of dickkopf-1 concentrations in plasma and synovial fluid to the severity of radiographic signs of equine osteoarthritis.

The purpose of this study was to determine whether there was a correlation between circulating and intra-synovial Dkk-1 and radiographic signs of equine osteoarthritis. Circulating and intra-synovial Dkk-1 levels were measured in clinical cases using a commercially available human Dkk-1 ELISA. Radiographs were performed of the joints from which fluid was collected and these were assessed and scored by a boarded radiologist for joint narrowing, subchondral bone sclerosis, subchondral bone lysis, and periarticular modelling. Comparisons were made between radiographic scores and the concentrations of Dkk-1 using a Kruskal-Wallis one-way ANOVA. Correlations were calculated using Kendall's statistic. A total of 42 synovial fluid samples from 21 horses were collected and used in the analysis. No significant correlation was identified between Dkk-1 concentrations and radiographic signs of osteoarthritis. Intra-synovial Dkk-1 concentrations were significantly greater (p <0.001) in low motion joints (mean concentration, 232.68 pg/mL; range, 109.07-317.17) when compared to high-motion joints (28.78 pg/mL; 0.05-186.44 pg/mL) (p <0.001). Low motion joints have significantly higher concentrations of Dkk-1 compared to high motion joints. Further research is needed to establish the importance of this finding and whether potential diagnostic or therapeutic applications of Dkk-1 exist in the horse.

Oleuropein inhibits the IL-1β-induced expression of inflammatory mediators by suppressing the activation of NF-κB and MAPKs in human osteoarthritis chondrocytes.

Osteoarthritis (OA) is the most common form of joint disease and is widespread in the elderly population and is characterized by erosion of articular cartilage, subchondral bone sclerosis and synovitis. Oleuropein (OL), a secoiridoid, is considered as the most prevalent phenolic component in olive leaves and seeds, pulp and peel of unripe olives and has been shown to have potent anti-inflammatory effects. However, its effects on OA have not been clearly elucidated. This study aimed to assess the effect of OL on human OA chondrocytes. Human OA chondrocytes were pretreated with OL (10, 50 and 100 μM) for 2 h and subsequently stimulated with IL-1β for 24 h. The production of NO, PGE2, MMP-1, MMP-13, and ADAMTS-5 was evaluated by the Griess reaction and ELISA assays. The messenger RNA (mRNA) expression of COX-2, iNOS, MMP-1, MMP13, ADAMTS-5, aggrecan, and collagen-II was measured by using real-time PCR. The protein expressions of COX-2, iNOS, p65, IκB-α, JNK, p-JNK, ERK, p-ERK, p38, and p-p38 were tested by using western blot. We found that OL significantly inhibited the IL-1β-induced production of NO and PGE2; expression of COX-2, iNOS, MMP-1, MMP-13, and ADAMTS-5; and degradation of aggrecan and collagen-II. Furthermore, OL dramatically suppressed IL-1β-stimulated NF-κB and MAPK activation. Immunofluorescence staining demonstrated that OL could suppress IL-1β-induced phosphorylation of p65 nuclear translocation. These results indicate that the therapeutic effect of OL on OA is accomplished through the inhibition of both NF-κB and MAPK signaling pathways. Altogether, our findings provide the evidence to develop OL as a potential therapeutic agent for patients with OA.

Topographic MRI evaluation of the sacroiliac joints in patients with axial spondyloarthritis

ObjectiveTo evaluate the imaging features of spondyloarthritis in magnetic resonance imaging (MRI) of the sacroiliac (SI) joint and topography (in thirds) and affected margin, considering that this issue is rarely addressed in the literature. MethodsA cross-sectional study evaluating MRI (1.5T) of SI in 16 patients with axial spondyloarthritis, for the presence of acute (subchondral bone edema, enthesitis, synovitis and capsulitis) and chronic (erosions, subchondral bone sclerosis, bony bridges, and fatty infiltration) changes, performed by two blinded radiologists. MRI findings were correlated with clinical data, including age, duration of disease, medications, HLA-B27, BASDAI, ASDAS-ESR and ASDAS-CRP, BASMI, BASFI, and mSASSS. ResultsBone edema pattern and erosions were predominant in the upper third of SI (p=0.050 and p=0.0014, respectively). There was a correlation between disease duration and structural changes by affected third (p=0.028–0.037), as well as between the presence of bone bridges with BASMI (p=0.028) and mSASSS (p=0.014). Patients with osteitis in the lower third showed higher values for ASDAS (ESR: p=0.011 and PCR: p=0.017). ConclusionChronic inflammatory changes and the pattern of bone edema predominated in the upper third of SI, but a simultaneous involvement of middle or lower thirds of the joint was also noted. The location of involvement in the upper third of SI is insufficient to differentiate between degeneration and inflammation.

Research progress of bisphosphonates in the treatment of osteoarthritis

Osteoarthritis is clinical common disease,radiography shows articular cartilage damaging, joint space narrowing, sclerosis of subchondral bone. The main pathological changes includes cartilage degeneration, joint edge and subchondral bone hyperplasia of reactivity. Osteoarthritis tends to slow development, generally treated by conservative management. However there is no cure about conservative treatment. The conservative treatment of osteoarthritis mainly includes physical healing, anti-inflammatory analgesic therapy, cartilage protective treatment. Recently, there are a few new ideas about the pathogenesis of OA, mainly considered OA occurred not only with the cartilage degenerative lesion caused the subchondral bone changes, but also subchondral bone metabolic abnormalities leading to cartilage injury biomechanics structural abnormalities (cartilage attached). In addition,studies have found that the subchondral bone changed osteoclasts in patients with OA, therefore bisphosphonates were used in the treatment of OA. Bishosphonates is a effective inhibitors of bone resorption, inhibiting osteoclast activity and subchondral bone bone metabolic abnormalities, delay cartilage degeneration of articular cartilage; In addition bishosphonates can inhibit articular cartilage bone mass loss, maintain the subchondral bone microstructure and joint function, reduce joint pain. Bishosphonates show positive results in the animal OA model, accompanied with clinical practice.In this paper, we discuss bishosphonates for the treatment of knee osteoarthritis and improvement of clinical symptoms.

Improved radiological diagnosis of palmar osteochondral disease in the Thoroughbred racehorse.

Palmar osteochondral disease (POD) is common in the Thoroughbred racehorse yet difficult to diagnose by radiography alone. To improve the sensitivity and specificity for diagnosing POD from radiographs. Prospective, longitudinal study. Radiographs in nine different projections were made of metacarpophalangeal joints (MCPJ) of 50 Thoroughbreds. Post-mortem, MCPJs were dissected and gross pathology was scored. Three experienced Thoroughbred clinicians read each radiograph and recorded their findings. Another clinician reviewed each radiograph alongside the related gross specimens in order to correlate radiological findings with joint pathology. This served as a 'gold standard'. The performance of each clinician at detecting POD was compared with the 'gold standard'. Radiological features associated with POD were identified and presented to the clinicians in a training manual, prior to them re-reading the radiographs. The ability of each clinician to diagnose POD was reassessed. Palmar osteochondral disease was a common finding (88/100 joints). All three clinicians demonstrated low sensitivity and low specificity at detecting POD (mean 0.37 and 0.75, respectively). Conversely, the sensitivity and specificity for POD in the 'gold standard' was high (0.95 and 1.0). POD was associated with primary radiological features (e.g. focal radiolucencies in the palmar condyles, disruption of the outline of subchondral bone and focal sclerosis of the palmar condyles) and secondary features (e.g. basilar and apical osteophytes on the proximal sesamoid bones, flattening of the palmar condyles and cavitation of the dorso-distal aspect of the third metacarpal bone). Secondary radiographic features were often easier to detect. Following training the performance of clinicians at identifying POD was significantly improved. Only two clinicians completed the study; low proportion of POD negative cases in the study. Clinicians frequently overlook key radiological features related to POD. Alerting clinicians to relevant radiological features improved the sensitivity and specificity of diagnosis.

Avaliação topográfica das articulações sacroilíacas por ressonância magnética em pacientes com espondiloartrite axial

ObjectiveTo evaluate the imaging features of spondyloarthritis in magnetic resonance imaging (MRI) of the sacroiliac (SI) joint, topography (in thirds) and affected margin, considering that this issue is rarely addressed in the literature. MethodsCross‐sectional study evaluating MRI (1.5T) of SI joints in 16 patients with axial spondyloarthritis for the presence of acute changes (subchondral bone edema, enthesitis, synovitis and capsulitis) and chronic changes (erosions, subchondral bone sclerosis, bony bridges, and fatty infiltration), performed by two radiologists blind for clinical data. MRI findings were correlated with clinical data, including age, duration of disease, medications, HLA‐B27, BASDAI, ASDAS‐ESR and ASDAS‐CRP, BASMI, BASFI, and mSASSS. ResultsBone edema and erosions were predominant in the upper third of SI joints (p=0.050 and p=0.0014, respectively). There was a correlation between disease duration and structural changes by affected third (p=0.028‐0.037), as well as between the presence of bony bridges with BASMI (p=0.028) and mSASSS (p=0.014). Patients with osteitis in the lower third showed higher values of ASDAS (ESR: p=0.011 and PCR: p=0.017). ConclusionChronic inflammatory changes and bone edema predominated in the upper third of SI joints, but a simultaneous involvement of middle or lower thirds of the joint was also noted. The location of involvement in the upper third of SI joints is insufficient to differentiate between degeneration and inflammation.