This study provides recommendations on the position of the implant in reverse shoulder replacement in order to minimise scapular notching and osteophyte formation. Radiographs from 151 patients who underwent primary reverse shoulder replacement with a single prosthesis were analysed at a mean follow-up of 28.3 months (24 to 44) for notching, osteophytes, the position of the glenoid baseplate, the overhang of the glenosphere, and the prosthesis scapular neck angle (PSNA). A total of 20 patients (13.2%) had a notch (16 Grade 1 and four Grade 2) and 47 (31.1%) had an osteophyte. In patients without either notching or an osteophyte the baseplate was found to be positioned lower on the glenoid, with greater overhang of the glenosphere and a lower PSNA than those with notching and an osteophyte. Female patients had a higher rate of notching than males (13.3% vs 13.0%) but a lower rate of osteophyte formation (22.9% vs 50.0%), even though the baseplate was positioned significantly lower on the glenoid in females (p = 0.009) and each had a similar mean overhang of the glenosphere. Based on these findings we make recommendations on the placement of the implant in both male and female patients to avoid notching and osteophyte formation. Cite this article: Bone Joint J 2013;95-B:530–5

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial membrane inflammation, osteophyte formation, and subchondral bone sclerosis. Pathological changes in cartilage and subchondral bone are the main processes in OA. In recent decades, many studies have demonstrated that activin-like kinase 3 (ALK3), a bone morphogenetic protein receptor, is essential for cartilage formation, osteogenesis, and postnatal skeletal development. Although the role of bone morphogenetic protein (BMP) signalling in articular cartilage and bone has been extensively studied, many new discoveries have been made in recent years around ALK3 targets in articular cartilage, subchondral bone, and the interaction between the two, broadening the original knowledge of the relationship between ALK3 and OA. In this review, we focus on the roles of ALK3 in OA, including cartilage and subchondral bone and related cells. It may be helpful to seek more efficient drugs or treatments for OA based on ALK3 signalling in future

Senescent chondrocyte and subchondral osteoclast overburden aggravate inflammatory cytokine and pro-catabolic proteinase overproduction, accelerating extracellular matrix degradation and pain during osteoarthritis (OA). Fibronectin type III domain containing 5 (FNDC5) is found to promote tissue homeostasis and alleviate inflammation. This study aimed to characterize what role Fndc5 may play in chondrocyte aging and OA development. Serum and macroscopically healthy and osteoarthritic cartilage were biopsied from patients with knee OA who received total knee replacement. Murine chondrocytes were transfected with Fndc5 RNAi or cDNA. Mice overexpressing Fndc5 (Fndc5Tg) were operated to have destabilized medial meniscus mediated (DMM) joint injury as an experimental OA model. Cellular senescence was characterized using RT-PCR analysis of p16INK4A, p21CIP1, and p53 expression together with ß-galactosidase activity staining. Articular cartilage damage and synovitis were graded using OARSI scores. Osteophyte formation and mechanical allodynia were quantified using microCT imaging and von Frey filament, respectively. Osteoclast formation was examined using tartrate-resistant acid phosphatase staining. Senescent chondrocyte and subchondral osteoclast overburden together with decreased serum FNDC5 levels were present in human osteoarthritic cartilage. Fndc5 knockdown upregulated senescence program together with increased IL-6, MMP9 and Adamts5 expression, whereas Alcian blue-stained glycosaminoglycan production were inhibited. Forced Fndc5 expression repressed senescence, apoptosis and IL-6 expression, reversing proliferation and extracellular matrix production in inflamed chondrocytes. Fndc5Tg mice showed few OA signs, including articular cartilage erosion, synovitis, osteophyte formation, subchondral plate sclerosis and mechanical allodynia together with decreased IL-6 production and few senescent chondrocytes and subchondral osteoclast formation during DMM-induced joint injury. Mechanistically, Fndc5 reversed histone H3K27me3-mediated IL-6 transcription repression to reduce reactive oxygen species production. Fndc5 loss correlated with OA development. It was indispensable in chondrocyte growth and anabolism. This study sheds light onto the anti-ageing and anti-inflammatory actions of Fndc5 to chondrocytes; and highlights the chondroprotective function of Fndc5 to compromise OA

Objectives. The objectives of this study were: 1) to examine osteophyte formation, subchondral bone advance, and bone marrow lesions (BMLs) in osteoarthritis (OA)-prone Hartley guinea pigs; and 2) to assess the disease-modifying activity of an orally administered phosphocitrate ‘analogue’, Carolinas Molecule-01 (CM-01). Methods. Young Hartley guinea pigs were divided into two groups. The first group (n = 12) had drinking water and the second group (n = 9) had drinking water containing CM-01. Three guinea pigs in each group were euthanized at age six, 12, and 18 months, respectively. Three guinea pigs in the first group were euthanized aged three months as baseline control. Radiological, histological, and immunochemical examinations were performed to assess cartilage degeneration, osteophyte formation, subchondral bone advance, BMLs, and the levels of matrix metalloproteinse-13 (MMP13) protein expression in the knee joints of hind limbs. Results. In addition to cartilage degeneration, osteophytes, subchondral bone advance, and BMLs increased with age. Subchondral bone advance was observed as early as six months, whereas BMLs and osteophytes were both observed mainly at 12 and 18 months. Fibrotic BMLs were found mostly underneath the degenerated cartilage on the medial side. In contrast, necrotic BMLs were found almost exclusively in the interspinous region. Orally administered CM-01 decreased all of these pathological changes and reduced the levels of MMP13 expression. Conclusion. Subchondral bone may play a role in cartilage degeneration. Subchondral bone changes are early events; formation of osteophytes and BMLs are later events in the OA disease process. Carolinas Molecule-01 is a promising small molecule candidate to be tested as an oral disease-modifying drug for human OA therapy. Cite this article: Y. Sun, A. J. Kiraly, A. R. Sun, M. Cox, D. R. Mauerhan, E. N. Hanley Jr. Effects of a phosphocitrate analogue on osteophyte, subchondral bone advance, and bone marrow lesions in Hartley guinea pigs. Bone Joint Res 2018;7:157–165. DOI:10.1302/2046-3758.72.BJR-2017-0253

Osteoarthritis (OA) is a disease of the synovial joint with synovial inflammation, capsular contracture, articular cartilage degradation, subchondral sclerosis and osteophyte formation contributing to pain and disability. Transcriptomic datasets have identified genetic loci in hip and knee OA demonstrating joint specificity. A limited number of studies have directly investigated transcriptional changes in shoulder OA. Further, gene expression patterns of periarticular tissues in OA have not been thoroughly investigated. This prospective case control series details transcriptomic expression of shoulder OA by analysing periarticular tissues in patients undergoing shoulder replacement for OA as correlated with a validated patient reported outcome measure of shoulder function, an increasing (clinically worsening) QuickDASH score. We then compared transcriptomic expression profiles in capsular tissue biopsies from the OA group (N=6) as compared to patients undergoing shoulder stabilisation for recurrent instability (the control group, N=26). Results indicated that top ranked genes associated with increasing QuickDASH score across all tissues involved inflammation and response to stress, namely interleukins, chemokines, complement components, nuclear response factors and immediate early response genes. Some of these genes were upregulated, and some downregulated, suggestive of a state of flux between inflammatory and anti-inflammatory signalling pathways. We have also described gene expression pathways in shoulder OA not previously identified in hip and knee OA, as well as novel genes involved in shoulder OA

Development of osteoarthritis (OA) correlates with epigenetic alteration in chondrocytes. H3K27me3 demethylase UTX is known to regulate tissue homeostasis, but its role in the homeostasis of articulating joint tissue is poorly understood. Forced UTX expression upregulated H3K27me3 enrichment at the Sox9 promoter region to inhibit key extracellular matrix (ECM) molecules, like e.g. type II collagen, aggrecan, and glycosaminoglycans in articular chondrocytes. Utx loss in vitro altered the H3K27me3-binding epigenomic landscape, which contributes to mitochondrial activity, cellular senescence, and cartilage development. Functional target genes of Utx comprise insulin-like growth factor 2 (Igf2) and polycomb repressive complex 2 (PRC2) core components Eed and Suz12. Specifically, Utx deletion promoted Tfam transcription, mitochondrial respiration, ATP production and Igf2 transcription, but inhibited Eed and Suz12 expression. Igf2 inhibition or forced Eed or Suz12 expression increased H3K27 trimethylation and H3K27me3 enrichment at the Sox9 promoter, compromising Utx loss-induced ECM overproduction. Overexpression of Utx in murine knee joints aggravated OA development, including articular cartilage damage, synovitis, osteophyte formation, and subchondral bone loss. Transgenic mice with a chondrocytespecific Utx knockout develop thicker articular cartilage as compared to wild-type controls and show fewer gonarthrotic symptoms during destabilized medial meniscus- and collagenase-induced joint injury. In summary, UTX represses chondrocytic activity and accelerates cartilage degradation during OA, while Utx loss promotes cartilage integrity through epigenetic stimulation of mitochondrial biogenesis and Igf2 transcription. This highlights a novel noncanonical role of Utx that regulates articular chondrocyte anabolism and OA development

Summary Statement. Intra-articular injection of humanised monoclonal anti-VEGF antibody (Bevacizumab, Avastin®) in a osteoarthritis rabbit model is related to positive restorative effects in terms of histopathologic evaluation. Introduction. Vascular endothelial growth factor (VEGF) is generally undetectable in adult human articular cartilage under physiological conditions. Upon exposure to pathological stimulation such as inflammation, hypoxia or accumulating mechanical stress, VEGF would be up regulated in hypertrophic chondrocytes of arthritic cartilage leading to osteophyte formation, disregulation of chondrocyte apoptosis and induction of catabolic factors, including matrix metalloproteinases (MMPs). This in vivo study aims to investigate the potential role of VEGF inhibition to treat Osteoarthritis (OA), through intra-articular injection of Bevacizumab, a humanised monoclonal anti-VEGF antibody, in a OA rabbit model. Methods. OA was induced in twelve adult male New Zealand rabbits surgically by monolateral Anterior Cruciate Ligament Transection (ACLT). The rabbits were randomly divided into two equal groups (experimental and control). Intra-articular injections of Bevacizumab or saline (control) were given 4 weeks after ACLT and were administered once a week for 4 time. Animal were sacrificed at 2 and 3 month time point an knee analyzed histologically and grossly. Histopathological variables such as the number of fibroblasts and inflammatory cells, collagenous matrix deposition, synovial hyperplasia, granulation tissue formation, vascular proliferation were evaluated. Results:The macroscopic evaluation of the knee in the experimental group revealed smooth joint surfaces of articular cartilage and no osteophyte formation compared to the control group that showed marked arthritis including synovial hypertrophy and osteophyte formation. Histologic assessment demonstrated, in the experimental group, significantly higher scores concerning number of microvessels, synovial hyperplasia, macrophage infiltration, collagenous matrix deposition, chondrocytes proliferation and apoptosis compared to the control group. Conclusion. In conclusion, VEGF modulation via intra-articular injection of Bevacizumab in a rabbit model of knee OA, resulted in reduction of articular cartilage degeneration through setting up an appropriate environment that prevent chondrocyte hypertrophy, apoptosis and osteophytes formation by blocking the intrinsic VEGF catabolic pathway, endochondral ossification, and the extrinsic VEGF-induced vascular invasion. VEGF-signaling inhibtion through Bevacizumab represent a potential way to treat OA

Osteoarthritis, the most common degenerative joint disease, significantly impairs life quality and labor capability of patients. Synovial inflammation, initiated by HMGB1 (High mobility group box 1)-induced activation of macrophage, precedes other pathological changes. As an upstream regulator of NF-κB (nuclear factor-kappa B) and MAPK (mitogen-activated protein kinase) signaling pathway, TAK1 (TGF-β activated kinase 1) participates in macrophage activation, while its function in osteoarthritis remains unveiled. This study aims to investigate the role of TAK1 in the pathogenesis of osteoarthritis via both in vitro and in vivo approaches. We performed immunohistochemical staining for TAK1 in synovial tissue, both in osteoarthritis patients and healthy control. Besides, immunofluorescence staining for F4/80 as macrophage marker and TAK1 were conducted as well. TAK1 expression was examined in RAW264.7 macrophages stimulated by HMGB1 via qPCR (Quantitative polymerase chain reaction) and Western blotting, and the effect of TAK1 inhibitor (5z-7 oxozeaenol) on TNF-α production was evaluated by immunofluorescence staining. Further, we explored the influence of intra-articular shRNA (short hairpin RNA) targeting TAK1 on collagenase-induced osteoarthritis in mice. Immunohistochemical staining confirmed significant elevation of TAK1 in osteoarthritic synovium, and immunofluorescence staining suggested macrophages as predominant residence of TAK1. In HMGB1-stimulated RAW264.7 macrophages, TAK1 expression was up-regulated both in mRNA and protein level. Besides, TAK1 inhibitor significantly impairs the production of TNF-α by macrophages upon HMGB1 stimulation. Moreover, intra-articular injection of lentivirus loaded with shRNA targeting TAK1 (sh-TAK1) reduced peri-articular osteophyte formation in collagenase-induced osteoarthritis in mice. TAK1 exerts a potent role in the pathogenesis of osteoarthritis by mediating the activation of macrophages

In osteoarthritis, chondrocytes acquire a hypertrophic phenotype that contributes to matrix degradation. Inflammation is proposed as trigger for the shift to a hypertrophic phenotype. Using in vitro culture of human chondrocytes and cartilage explants we could not find evidence for a role of inflammatory signalling activation. We found, however, that tissue repair macrophages may contribute to the onset of hypertrophy (doi: 10.1177/19476035211021907) Intra-articularly injected triamcinolone acetonide to inhibit inflammation in a murine model of collagenase-induced osteoarthritis, increased synovial macrophage numbers and osteophytosis, confirming the role of macrophages in chondrocyte hypertrophy occurring in osteophyte formation (doi: 10.1111/bph.15780). In search of targets to inhibit chondrocyte hypertrophy, we combined existing microarray data of different cartilage layers of murine growth plate and murine articular cartilage after induction of collagenase-induced osteoarthritis. We identified common differentially expressed genes and selected those known to be associated to inflammation. This revealed EPHA2, a tyrosine kinase receptor, as a new target. Using in silico, in vitro and in vivo models we demonstrated that inhibition of EPHA2 might be a promising treatment for osteoarthritis. Recently, single cell RNA-seq. has revealed detailed information about different populations of chondrocytes in articular cartilage during osteoarthritis. We re-analysed a published scRNA-seq data set of healthy and osteoarthritic cartilage to obtain the differentially expressed genes in the population of hypertrophic chondrocytes compared to the other chondrocytes, applied pathway analyses and then used drug databases to search for upstream inhibitors of these pathways. This drug repurposing approach led to the selection of 6 drugs that were screened and tested using several in vitro models with human chondrocytes and cartilage explants. In this lecture I will present this sequence of studies to highlight different approaches and models that can be used in the quest for a disease modifying drug for osteoarthritis

Background. Intervertebral disc degeneration (DD) is a complex age-related condition that constitutes the main risk factor for disabling back pain. DD is assessed using different traits extracted from MR imaging (MRI), normally combined to give summary measures (e.g. Pfirmann score). The aetiology of DD is poorly understood and despite its high heritability (75%), the precise genetic predisposition is yet to be defined. Genome wide association study (GWAS) is used to discover genetic variants associated with a disease or phenotype. It tests variants across the whole genome. It requires large samples to provide adequate but unfortunately there is poor availability of spine imaging data due to the high cost of MRI. We have adopted new methods to examine different MRI traits independently and use the information of those traits to boost GWAS power using specialized statistical software for jointly analyse correlated traits. Methods/Results. We examined DD MRI features disc narrowing, disc bulge, disc signal intensity and osteophyte formation in the TwinsUK cohort who had undergone T2-weighted sagittal spine MRI. GWAS were performed on the four traits. MTAG software was used to boost single trait GWAS power using the information in the other trait GWAS. 9 different loci were identified. Conclusions. Preliminary results suggest genes GDF6, SP1/SP7 are associated with individual trait signal intensity. In addition, novel associated genes with potential for shedding new light on pathogenic mechanisms are identified. Additional cohorts will be included in the design as a replication to test reproducibility of the results. Conflicts of interest: No conflicts of interest. Sources of funding: Funded by Disc4All, EU Horizon 2020, MSCA-2020-ITN-ETN GA: 955735

Background. Lateral ankle instability is a common problem, but the precise role of the lateral ankle structures has not been accurately investigated. This study aimed to accurately investigate lateral ankle complex stability for the first time using a novel robotic testing platform. Method. A six degrees of freedom robot manipulator and a universal force/torque sensor were used to test 10 foot and ankle specimens. The system automatically defined the path of unloaded plantar/dorsi flexion. At four flexion angles: 20° dorsiflexion, neutral flexion, 20° and 40° of plantarflexion; anterior-posterior (90N), internal-external (5Nm) and inversion-eversion (8Nm) laxity were tested. The motion of the intact ankle was recorded first and then replayed following transection of the lateral retinaculum, Anterior Talofibular Ligament (ATFL) and Calcaneofibular Ligament (CFL). The decrease in force/torque reflected the contribution of the structure to restraining laxity. Data were analysed using repeated measures of variance and paired t-tests. Results. The ATFL was the primary restraint to anterior drawer (P< 0.01) and the CFL the primary restraint to inversion throughout range (P< 0.04), but with increased plantarflexion the ATFL's contribution increased. The ATFL had a significant role in resisting tibial external rotation, particularly at higher levels of plantarflexion, contributing 63% at 40° (P< 0.01). The CFL provided the greatest resistance to external tibial rotation, 22% at 40° plantarflexion (P< 0.01). The extensor retinaculum and skin did not offer significant restraint in any direction tested. Conclusion. This study shows accurately for the first time the significant role the ATFL and CFL have in rotational ankle stability. This significant loss in rotational stability may have implications in the aetiology of osteophyte formation and early degenerative changes in patients with chronic ankle instability. This is the first time the role of the lateral ankle complex has been quantified using a robotic testing platform

Osteophyte deposition and subchondral bone damage are notable features of osteoarthritis (OA). Deregulated mineralization contributes to osteophyte and subchondral irregularity. The microRNA-29 (miR-29) family is associated with arthritic disorders. This study is aimed to investigate miR-29a function to OA osteophyte formation and subchondral integrity. Intact and damaged articular cartilage in patients with end-stage knee OA who required total knee arthroplasty were harvested to probe miR-29a, cartilage, and mineralized matrix expression using RT-PCR and in situ hybridization. Osteophyte volume and subchondral morphometry of collagenase-induced OA knees in mice were quantified using μCT and histomorphometry. Increased bone matrix expression (collagen I and bone alkaline phosphatase) and reduced cartilage matrix (collagen II and aggrecan) along with low miR-29a expression existed in human OA specimens. Aged miR-29a knockout mice showed spontaneous osteophyte formation and articular cartilage erosion. In primary articular chondrocytes, miR-29a deficiency significantly reduced cartilage matrix synthesis, whereas von Kossa staining-positive mineralized matrix production was increased. Of interest, the severity of collagenase-induced osteophyte accumulation and subchondral damage along with serum cartilage breakdown products CTX-II and COMP levels were significantly compromised in mice overexpressing miR-29a. Intra-articularly injecting miR-29a significantly reduced osteophyte volume and subchondral integrity and retained cartilage morphology in collagenase-injured knees. Reduced miR-29a signalling worsens osteophyte and subchondral destruction in OA through increasing mineralized matrix formation of chondrocytes. Restoring miR-29a shields joints from cartilage degradation, osteophyte and subchondral destruction. This study conveys new mechanistic underlying OA osteophyte pathogenesis and shines light on the remedial potential of miR-29a to OA

Knowledge of the premorbid glenoid shape and the morphological changes the bone undergoes in patients with glenohumeral arthritis can improve surgical outcomes in total and reverse shoulder arthroplasty. Several studies have previously used scapular statistical shape models (SSMs) to predict premorbid glenoid shape and evaluate glenoid erosion properties. However, current literature suggests no studies have used scapular SSMs to examine the changes in glenoid surface area in patients with glenohumeral arthritis. Therefore, the purpose of this study was to compare the glenoid articular surface area between pathologic glenoid cavities from patients with glenohumeral arthritis and their predicted premorbid shape using a scapular SSM. Furthermore, this study compared pathologic glenoid surface area with that from virtually eroded glenoid models created without influence from internal bone remodelling activity and osteophyte formation. It was hypothesized that the pathologic glenoid cavities would exhibit the greatest glenoid surface area despite the eroded nature of the glenoid and the medialization, which in a vault shape, should logically result in less surface area. Computer tomography (CT) scans from 20 patients exhibiting type A2 glenoid erosion according to the Walch classification [Walch et al., 1999] were obtained. A scapular SSM was used to predict the premorbid glenoid shape for each scapula. The scapula and humerus from each patient were automatically segmented and exported as 3D object files along with the scapular SSM from a pre-operative planning software. Each scapula and a copy of its corresponding SSM were aligned using the coracoid, lateral edge of the acromion, inferior glenoid tubercule, scapular notch, and the trigonum spinae. Points were then digitized on both the pathologic humeral and glenoid surfaces and were used in an iterative closest point (ICP) algorithm in MATLAB (MathWorks, Natick, MA, USA) to align the humerus with the glenoid surface. A Boolean subtraction was then performed between the scapular SSM and the humerus to create a virtual erosion in the scapular SSM that matched the erosion orientation of the pathologic glenoid. This led to the development of three distinct glenoid models for each patient: premorbid, pathologic, and virtually eroded (Fig. 1). The glenoid surface area from each model was then determined using 3-Matic (Materialise, Leuven, Belgium). Figure 1. (A) Premorbid glenoid model, (B) pathologic glenoid model, and (C) virtually eroded glenoid model. The average glenoid surface area for the pathologic scapular models was 70% greater compared to the premorbid glenoid models (P < 0 .001). Furthermore, the surface area of the virtual glenoid erosions was 6.4% lower on average compared to the premorbid glenoid surface area (P=0.361). The larger surface area values observed in the pathologic glenoid cavities suggests that sufficient bone remodelling exists at the periphery of the glenoid bone in patients exhibiting A2 type glenohumeral arthritis. This is further supported by the large difference in glenoid surface area between the pathologic and virtually eroded glenoid cavities as the virtually eroded models only considered humeral anatomy when creating the erosion. For any figures or tables, please contact the authors directly

Aim. Mesenchymal stem cells (MSCs) have several properties that may support their use as an early treatment option for osteoarthritis (OA). This study investigated the role of multiple injections of allogeneic bone marrow-derived stem cells (BMSCs) to alleviate the progression of osteoarthritic changes in the various structures of the mature rabbit knee in an anterior cruciate ligament (ACL)-deficient OA model. Materials and Methods. Two months after bilateral section of the ACL of Japanese white rabbits aged nine months or more, either phosphate buffered saline (PBS) or 1 x 10. 6. MSCs were injected into the knee joint in single or three consecutive doses. After two months, the articular cartilage and meniscus were assessed macroscopically, histologically, and immunohistochemically using collagen I and II. Results. Within the PBS injection (control group), typical progressive degenerative changes were revealed in the various knee structures. In the single MSC injection (single group), osteoarthritic changes were attenuated, but still appeared, especially in the medial compartments involving fibrillation of the articular cartilage, osteophyte formation in the medial plateau, and longitudinal tear of the meniscus. In the multiple-injections group, the smoothness and texture of the articular cartilage and meniscus were improved. Histologically, absence or reduction in matrix staining and cellularity were noticeable in the control and single-injection groups, respectively, in contrast to the multiple-injections group, which showed good intensity of matrix staining and chondrocyte distribution in the various cartilage zones. Osteoarthritis Research Society International (OARSI) scoring showed significantly better results in the multiple-injections group than in the other groups. Immunohistochemically, collagen I existed superficially in the medial femoral condyle in the single group, while collagen II was more evident in the multiple-injections group than the single-injection group. Conclusion. A single injection of MSCs was not enough to restore the condition of osteoarthritic joints. This is in contrast to multiple injections of MSCs, which had the ability to replace lost cells, as well as reducing inflammation. Cite this article: Bone Joint J 2019;101-B:824–831

Introduction and Objective. Osteoarthristis (OA) has been associated with many genes and yet the genetic basis for this disease has never formally been established. Recent realization that epigenetic changes could be the underlying pathological mechanisms has helped to explain many complex multifactorial diseases with no clear genetic cause. We therefore asked whether epigenetics could also play a role in OA. We have previously shown that the DNA epigenetic modification, specifically the hydroxymethylation on cytosine (5hmC), undergoes a fivefold increase on OA-associated genes which are activated at OA onset. In this study, we further uncovered a set of 5hmC-mediated gene targets and their mechanistic link to OA progression. Materials and Methods. We surgically induced OA on 4 to 6 months old Tet1−/− mice (Tet1tm1.1Jae, the Jackson laboratory) and wild-type littermates by performing destabilization of the medial meniscus (DMM) surgery. Joints were collected for histological assessment through blinded grading with the OARSI scoring system. Human articular chondrocytes were harvested from OA cartilage samples obtained during total knee arthroplasty or from grossly normal cartilage pieces obtained during notchplasty or debridement from patients undergoing anterior cruciate ligament (ACL) reconstruction with no history of OA symptoms, under approved Human subjects Institutional Review Board protocols. Bioinformatic analyses of RNA-sequencing and CCGG sequencing (reduced representation 5hmC profiling) were performed to identify TET1 target genes associated with OA progression. Several measurements were used to assess the effect of TET1 ablation on the phenotype of mouse cartilage tissue and human chondrocytes including, histological evaluation, and quantitative bone assessment by micro-CT imaging and multiplex cytokine analyses in the serum of mice in vivo (mouse 39-plex assay) and in the supernatant of human chondrocyte cultures (human 62-plex assay). Results. We used a mouse model with surgically induced OA and found that OA onset was accompanied by a gain of ∼40,000 differentially hydroxymethylated sites prior the notable histological onset of the disease. We additionally revealed that these changes are mediated by the ten-eleven-translocation enzyme 1 (TET1), since Tet1−/− mice lost 98% of 5hmC sites upon OA induction. Remarkably, Tet1−/− mice were protected from OA development including degeneration of the cartilage surface and osteophyte formation. Silencing of TET1 expression in human OA chondrocytes reduced the expression in a set of genes, which may represent the pathological gene targets that exacerbate OA including MMP3 and MMP13 and several inflammatory cytokines. Therefore, our study reveals the unexpected beneficial role of TET1 inhibition in blocking OA progression. In fact, intra-articular injections of a dioxygenases’ inhibitor, 2 hydroxyglutarate, on mice after surgical induction of OA stalled disease progression. Furthermore, treatment of human OA chondrocytes with the same inhibitor also phenocopied TET1 loss, implicating a therapeutic potential of TET inhibition in OA patients. Conclusions. Collectively, our study not only demonstrate the role of TET1 in OA; the 5hmC-mediated gene targets acting on multiple OA pathways were identified and can be modulated as therapeutic intervention to treat OA

Cartilage neoangiogenesis holds a key role in the development of osteoarthritis (OA) by promoting cartilage degradation with proteoglycan loss, subchondral bone sclerosis, osteophyte formation and synovial hyperplasia. This study aimed to assess the in vivo efficacy of bevacizumab, an antibody against vascular endothelial growth factor (VEGF) in an OA animal model. 24 New Zealand white rabbits underwent anterior cruciate ligament transection in order to spontaneously develop knee OA. Animals were divided into four groups: one receiving a sham intraarticular knee injection (saline) and three groups treated with 5, 10, and 20 mg intraarticular bevacizumab injections. The biological effect of the antibody on cartilage and synovium was evaluated through histology and quantified with the Osteoarthritis Research Society International (OARSI) scores. Immunohistochemical analysis was conducted to investigate type 2 collagen, aggrecan, and matrix metalloproteinase 13 (MMP-13) expression in both cartilage and synovium. Intraarticular bevacizumab led to a significant reduction of cartilage degeneration and synovial OA alterations. Immunohistochemistry showed a significantly reduced MMP-13 expression in all experimental groups, with the one receiving 20 mg bevacizumab showing the lowest. Furthermore, the antibody showed to increment the production of aggrecan and type 2 collagen after administration of 5, 10, and 20 mg. The group treated with 20 mg showed the highest levels of type 2 collagen expression, while aggrecan content was even higher than in the healthy cartilage. Intraarticular bevacizumab has demonstrated to effectively arrest OA progression in our model, with 20 mg being the most efficacious dose. By inhibiting cartilage and synovial neoangiogenesis, bevacizumab may serve as a possible disease-modifying osteoarthritis drug (DMOAD) in the next future

Osteoarthritis (OA) is a chronic degenerative joint disease with cartilage degeneration, subchondral bone sclerosis, synovial inflammation and osteophyte formation. Sensory nerves play an important role in bone metabolism and in the progression of inflammation. This study explored the effects of capsaicin-induced sensory nerve denervation on OA progression in mice. This study was approved by the Institutional Animal Care and Use Committee. OA was induced via destabilization of the medial meniscus (DMM). Sensory denervation was induced by subcutaneous injection of capsaicin (90mg/kg) one week prior to DMM. One week after capsaicin injection, sensory denervation in the tibia was confirmed by immunofluorescent staining with calcitonin gene-related peptide (CGRP)-specific antibodies. Four weeks after DMM, micro-CT scans, histological analysis and RT-PCR tests were performed to evaluate OA progression. Statistical analysis was performed using SPSS 13. P values of less than 0.05 were considered statistically significant. Subcutaneous injection of capsaicin successfully induced tibial sensory denervation (n=3), which aggravated OA by increasing subchondral bone resorption. The Osteoarthritis Research Society International (OARSI) score of the capsaicin+DMM group (n=8) (11.81±2.92) was significantly higher (P=0.003) than the score of the vehicle+DMM group (n=8) (8.31±1.80). The BV/TV of the tibial subchondral bone in the capsaicin+DMM group (n=8) was 55.67%±3.08, which was significantly lower (P < 0 .001) than in the vehicle+DMM group (n=8) (86.22%±1.92). In addition, the level of expression of somatostatin in the capsaicin+DMM group (n=8) was lower than in the vehicle+DMM group (n=8) (P=0.007). Capsaicin-induced sensory denervation increased tibial subchondral bone resorption, reduced the expression of somatostatin and eventually exacerbated the existing cartilage degeneration in mice. Despite capsaicin is often used clinically to relieve OA pain, its safety is still controversial according to the OARSI guidelines for the non-surgical management of knee osteoarthritis. The findings of our study suggest that application of capsaicin, although effective in relieving pain, may accelerate the progression of existing OA

We investigated the association between the radiological findings and the symptoms arising from the patellofemoral joint in advanced osteoarthritis (OA) of the knee. Four radiological features, joint space narrowing, osteophyte formation, translation of the patella and focal attrition were assessed in 151 consecutive osteoarthritic knees in 107 patients undergoing total knee replacement. The symptoms which were assessed included anterior knee pain which was scored, the ability to rise from a chair and climb stairs, and quadriceps weakness. Among the radiological features, only patellar translation and obliteration of the joint space had a statistically significant association with anterior knee pain (odds ratio (OR) 4.85; 95% confidence interval (CI) 1.83 to 12.88 and OR 11.23; 95% CI 2.44 to 51.62) respectively. Patellar translation had a statistically significant association with difficulty in rising from a chair (OR 9.06; 95% CI 1.75 to 45.11). Other radiological features, including osteophytes, joint space narrowing, and focal attrition had no significant association. Our study indicates that the radiological findings of patellar translation and significant loss of cartilage are predictive of patellofemoral symptoms and functional limitation in advanced OA of the knee

Introduction. Osteoarthritis (OA) is a progressively debilitating disease that affects mostly cartilage, with associated changes in the bone. The increasing incidence of OA and an ageing population, coupled with insufficient therapeutic choices, has led to focus on the potential of stem cells as a novel strategy for cartilage repair. Methods. In this study, we used scaffold-free mesenchymal stem cells (MSCs) obtained from bone marrow in an experimental animal model of OA by direct intra-articular injection. MSCs were isolated from 2.8 kg white New Zealand rabbits. There were ten in the study group and ten in the control group. OA was induced by unilateral transection of the anterior cruciate ligament of the knee joint. At 12 weeks post-operatively, a single dose of 1 million cells suspended in 1 ml of medium was delivered to the injured knee by direct intra-articular injection. The control group received 1 ml of medium without cells. The knees were examined at 16 and 20 weeks following surgery. Repair was investigated radiologically, grossly and histologically using haematoxylin and eosin, Safranin-O and toluidine blue staining. Results. Radiological assessment confirmed development of OA changes after 12 weeks. Rabbits receiving MSCs showed a lower degree of cartilage degeneration, osteophyte formation, and subchondral sclerosis than the control group at 20 weeks post-operatively. The quality of cartilage was significantly better in the cell-treated group compared with the control group after 20 weeks. Conclusions. Bone marrow-derived MSCs could be promising cell sources for the treatment of OA. Neither stem cell culture nor scaffolds are absolutely necessary for a favourable outcome. Cite this article: Bone Joint Res 2014;3:32–7

The purpose of current study was to describe the results of complex acetabular fractures treated with open reduction using transtrochanteric approach and arthrotomy of the hip joint. Fourteen consecutive patients with both column fractures of the acetabulum were treated with open reduction and internal fixation. All patients had various associated injuries. Among them, one patient had pelvic abscess associated with traumatic bowel perforation. The acetabulum was approached with Y-shaped triradiate incision, osteotomy of the greater trochanter, and arthrotomy of the hip joint. During the operation, the osteochondral fragments were removed and torn labrum was resected. In 6 patients the fracture was fixed with reconstruction plates and in 8 patients the fracture was fixed with plates and wires. All the patients were followed for an average of 4.6 years(range, 2–8 years). The clinical evaluation was done by the method of Merle d’Aubigne. All the fractures and all osteotomies united at the latest follow up. One patient had delayed hematogenous infection at 5.5 years after the operation. Although myositis ossificans developed in 3 patients it was neither progressive after 1 year nor associated with significant limitation of hip motion. Four patients had narrowing of the hip joint space. Three of them had osteophyte formation around the femoral head. No femoral head necrosis was observed. Eleven patients had excellent or good outcomes in clinical score. No patient underwent total hip arthroplasty. This extensile approach allowed a good exposure of the fracture site, more accurate reduction, and easier fixation of fracture fragments. It also allowed the removal of osteochondral fragments and the resection of torn labrum. However, 3 patients showed osteophyte formation around the femoral head. We are concerned about the further progression of the osteophyte and its clinical implication