Aims. Recent studies have suggested that corticosteroid injections into the knee may harm the joint resulting in cartilage loss and possibly accelerating the progression of osteoarthritis (OA). The aim of this study was to assess whether patients with, or at risk of developing, symptomatic osteoarthritis of the knee who receive intra-articular corticosteroid injections have an increased risk of requiring arthroplasty. Methods. We used data from the Osteoarthritis Initiative (OAI), a multicentre observational cohort study that followed 4,796 patients with, or at risk of developing, osteoarthritis of the knee on an annual basis with follow-up available up to nine years. Increased risk for symptomatic OA was defined as frequent knee symptoms (pain, aching, or stiffness) without radiological evidence of OA and two or more risk factors, while OA was defined by the presence of both femoral osteophytes and frequent symptoms in one or both knees. Missing data were imputed with multiple imputations using chained equations. Time-dependent propensity score matching was performed to match patients at the time of receving their first injection with controls. The effect of corticosteroid injections on the rate of subsequent (total and partial) knee arthroplasty was estimated using Cox proportional-hazards survival analyses. Results. After removing patients lost to follow-up, 3,822 patients remained in the study. A total of 249 (31.3%) of the 796 patients who received corticosteroid injections, and 152 (5.0%) of the 3,026 who did not, had knee arthroplasty. In the matched cohort, Cox proportional-hazards regression resulted in a hazard ratio of 1.57 (95% confidence interval (CI) 1.37 to 1.81; p < 0.001) and each injection increased the absolute risk of arthroplasty by 9.4% at nine years’ follow-up compared with those who did not receive injections. Conclusion. Corticosteroid injections seem to be associated with an increased risk of knee arthroplasty in patients with, or at risk of developing, symptomatic OA of the knee. These findings suggest that a conservative approach regarding the treatment of these patients with corticosteroid injections should be recommended. Cite this article: Bone Joint J 2020;102-B(5):586–592

Objectives. Given the function of adiponectin (ADIPOQ) on the inflammatory condition of obesity and osteoarthritis (OA), we hypothesized that the ADIPOQ gene might be a candidate gene for a marker of susceptibility to OA. Methods. We systematically screened three tagging polymorphisms (rs182052, rs2082940 and rs6773957) in the ADIPOQ gene, and evaluated the association between the genetic variants and OA risk in a case-controlled study that included 196 OA patients and 442 controls in a northern Chinese population. Genotyping was performed using the Sequenom MassARRAY iPLEX platform. Results. The single nucleotide polymorphism (SNP) rs182052 was found to be potentially associated with knee OA risk (additive model: odds ratio = 1.38; 95% confidence interval 1.07 to 1.76; p = 0.012). Furthermore, a non-significant association was observed for rs182052 and body mass index with regard to OA risk in interaction analyses (p = 0.063). Similarly, no significant interaction was detected for rs182052 and age with regard to OA risk (p = 0.614). Conclusion. These findings suggest that the SNP rs182052 in the ADIPOQ gene may potentially modify individual susceptibility to knee OA in the Chinese population. Further studies are warranted to investigate our findings in more depth. Cite this article: L. Jiang, X. Zhu, J. Rong, B. Xing, S. Wang, A. Liu, M. Chu, G. Huang. Obesity, osteoarthritis and genetic risk: The rs182052 polymorphism in the ADIPOQ gene is potentially associated with risk of knee osteoarthritis. Bone Joint Res 2018;7:494–500. DOI: 10.1302/2046-3758.77.BJR-2017-0274.R1

Aims. Altered alignment and biomechanics are thought to contribute to the progression of osteoarthritis (OA) in the native compartments after medial unicompartmental knee arthroplasty (UKA). The aim of this study was to evaluate the bone activity and remodelling in the lateral tibiofemoral and patellofemoral compartment after medial mobile-bearing UKA. Patients and Methods. In total, 24 patients (nine female, 15 male) with 25 medial Oxford UKAs (13 left, 12 right) were prospectively followed with sequential 99mTc-hydroxymethane diphosphonate single photon emission CT (SPECT)/CT preoperatively and at one and two years postoperatively, along with standard radiographs and clinical outcome scores. The mean patient age was 62 years (40 to 78) and the mean body mass index (BMI) was 29.7 kg/m2 (23.6 to 42.2). Mean osteoblastic activity was evaluated using a tracer localization scheme with volumes of interest (VOIs). Normalized mean tracer values were calculated as the ratio between the mean tracer activity in a VOI and background activity in the femoral diaphysis. Results. Significant reduction of normalized tracer activity was observed one year postoperatively in tibial and femoral VOIs adjacent to the joint line in the lateral compartment. Patellar VOIs and remaining femoral VOIs demonstrated a significant, diminished normalized tracer activity at final follow-up. Conclusion. The osteoblastic bone activity in the native compartments decreased significantly after treatment of medial end-stage OA with a UKA, implying reduced stress to the subchondral bone in the retained compartments after a UKA. Cite this article: Bone Joint J 2019;101-B:915–921

Objectives. Adult mice lacking the transcription factor NFAT1 exhibit osteoarthritis (OA). The precise molecular mechanism for NFAT1 deficiency-induced osteoarthritic cartilage degradation remains to be clarified. This study aimed to investigate if NFAT1 protects articular cartilage (AC) against OA by directly regulating the transcription of specific catabolic and anabolic genes in articular chondrocytes. Methods. Through a combined approach of gene expression analysis and web-based searching of NFAT1 binding sequences, 25 candidate target genes that displayed aberrant expression in Nfat1. -/-. AC at the initiation stage of OA, and possessed at least four NFAT1 binding sites in the promoter of each gene, were selected and tested for NFAT1 transcriptional activities by chromatin immunoprecipitation (ChIP) and promoter luciferase reporter assays using chondrocytes isolated from the AC of three- to four-month-old wild-type mice or Nfat1. -/-. mice with early OA phenotype. Results. Chromatin immunoprecipitation assays revealed that NFAT1 bound directly to the promoter of 21 of the 25 tested genes encoding cartilage-matrix proteins, growth factors, inflammatory cytokines, matrix-degrading proteinases, and specific transcription factors. Promoter luciferase reporter assays of representative anabolic and catabolic genes demonstrated that NFAT1-DNA binding functionally regulated the luciferase activity of specific target genes in wild-type chondrocytes, but not in Nfat1. -/-. chondrocytes or in wild-type chondrocytes transfected with plasmids containing mutated NFAT1 binding sequences. Conclusion. NFAT1 protects AC against degradation by directly regulating the transcription of target genes in articular chondrocytes. NFAT1 deficiency causes defective transcription of specific anabolic and catabolic genes in articular chondrocytes, leading to increased matrix catabolism and osteoarthritic cartilage degradation. Cite this article: M. Zhang, Q. Lu, T. Budden, J. Wang. NFAT1 protects articular cartilage against osteoarthritic degradation by directly regulating transcription of specific anabolic and catabolic genes. Bone Joint Res 2019;8:90–100. DOI: 10.1302/2046-3758.82.BJR-2018-0114.R1

Aims. To our knowledge, no study has compared the long-term results of cemented and hybrid total hip arthroplasty (THA) in patients with osteoarthritis (OA) secondary to congenital hip disease (CHD). This is a demanding procedure that may require special techniques and implants. Our aim was to compare the long-term outcome of cemented low-friction arthroplasty (LFA) and hybrid THA performed by one surgeon. Patients and Methods. Between January 1989 and December 1997, 58 hips (44 patients; one man, 43 woman; mean age 56.6 years (25 to 77)) with OA secondary to CHD were treated with a cemented Charnley LFA (group A), and 55 hips (39 patients; two men, 37 women; mean age 49.1 years (27 to 70)) were treated with a hybrid THA (group B), by the senior author (GH). The clinical outcome and survivorship were compared. Results. At all timepoints, group A hips had slightly better survivorship than those in group B without a statistically significant difference, except for the 24-year survival of acetabular components with revision for aseptic loosening as the endpoint, which was slightly worse. The survivorship was only significantly better in group A compared with group B when considering reoperation for any indication as the endpoint, 15 years postoperatively (74% vs 52%, p = 0.018). Conclusion. We concluded that there was not a substantial difference at almost any time in the outcome of cemented Charnley LFAs compared with hybrid THAs when treating patients with OA of the hip secondary to CHD. We believe, however, that after improvements in the design of components used in hybrid THA, this could be the method of choice, as it is technically easier with a shorter operating time. Cite this article: Bone Joint J 2019;101-B:1050–1057

Objectives. In this study, we compared the pain behaviour and osteoarthritis (OA) progression between anterior cruciate ligament transection (ACLT) and osteochondral injury in surgically-induced OA rat models. Methods. OA was induced in the knee joints of male Wistar rats using transection of the ACL or induction of osteochondral injury. Changes in the percentage of high limb weight distribution (%HLWD) on the operated hind limb were used to determine the pain behaviour in these models. The development of OA was assessed and compared using a histological evaluation based on the Osteoarthritis Research Society International (OARSI) cartilage OA histopathology score. Results. Both models showed an increase in joint pain as indicated by a significant (p < 0.05) decrease in the values of %HLWD at one week post-surgery. In the osteochondral injury model, the %HLWD returned to normal within three weeks, while in the ACLT model, a significant decrease in the %HLWD was persistent over an eight-week period. In addition, OA progression was more advanced in the ACLT model than in the osteochondral injury model. Furthermore, the ACLT model exhibited a higher mean OA score than that of the osteochondral injury model at 12 weeks. Conclusion. The development of pain patterns in the ACLT and osteochondral injury models is different in that the OA progression was significant in the ACLT model. Although both can be used as models for a post-traumatic injury of the knee, the selection of appropriate models for OA in preclinical studies should be specified and relevant to the clinical scenario. Cite this article: T. Tawonsawatruk, O. Sriwatananukulkit, W. Himakhun, W. Hemstapat. Comparison of pain behaviour and osteoarthritis progression between anterior cruciate ligament transection and osteochondral injury in rat models. Bone Joint Res 2018;7:244–251. DOI: 10.1302/2046-3758.73.BJR-2017-0121.R2

Aims. Limited evidence is available on mid-term outcomes of robotic-arm assisted (RA) partial knee arthroplasty (PKA). Therefore, the purpose of this study was to evaluate mid-term survivorship, modes of failure, and patient-reported outcomes of RA PKA. Methods. A retrospective review of patients who underwent RA PKA between June 2007 and August 2016 was performed. Patients received a fixed-bearing medial or lateral unicompartmental knee arthroplasty (UKA), patellofemoral arthroplasty (PFA), or bicompartmental knee arthroplasty (BiKA; PFA plus medial UKA). All patients completed a questionnaire regarding revision surgery, reoperations, and level of satisfaction. Knee Injury and Osteoarthritis Outcome Scores (KOOS) were assessed using the KOOS for Joint Replacement Junior survey. Results. Mean follow-up was 4.7 years (2.0 to 10.8). Five-year survivorship of medial UKA (n = 802), lateral UKA (n = 171), and PFA/BiKA (n = 35/10) was 97.8%, 97.7%, and 93.3%, respectively. Component loosening and progression of osteoarthritis (OA) were the most common reasons for revision. Mean KOOS scores after medial UKA, lateral UKA, and PFA/BiKA were 84.3 (SD 15.9), 85.6 (SD 14.3), and 78.2 (SD 14.2), respectively. The vast majority of the patients reported high satisfaction levels after RA PKA. Subgroup analyses suggested tibial component design, body mass index (BMI), and age affects RA PKA outcomes. Five-year survivorship was 98.4% (95% confidence interval (CI) 97.2 to 99.5) for onlay medial UKA (n = 742) and 99.1% (95% CI 97.9 to 100) for onlay medial UKA in patients with a BMI < 30 kg/m. 2. (n = 479). Conclusion. This large single-surgeon study showed high mid-term survivorship, satisfaction levels, and functional outcomes in RA UKA using metal-backed tibial onlay components. In addition, favourable results were reported in RA PFA and BiKA. Cite this article: Bone Joint J 2020;102-B(1):108–116

Aims. This study presents the long-term survivorship, risk factors for prosthesis survival, and an assessment of the long-term effects of changes in surgical technique in a large series of patients treated by metal-on-metal (MoM) hip resurfacing arthroplasty (HRA). Patients and Methods. Between November 1996 and January 2012, 1074 patients (1321 hips) underwent HRA using the Conserve Plus Hip Resurfacing System. There were 787 men (73%) and 287 women (27%) with a mean age of 51 years (14 to 83). The underlying pathology was osteoarthritis (OA) in 1003 (75.9%), developmental dysplasia of the hip (DDH) in 136 (10.3%), avascular necrosis in 98 (7.4%), and other conditions, including inflammatory arthritis, in 84 (6.4%). Results. The mean follow-up time was 10.5 years (1 to 20). Using revision for any reason as the endpoint, the overall survivorship at 15 years was 89.4% (95% confidence interval (CI) 86.8 to 91.4). There was a substantial increase between the first and second generation of surgical technique (86.6% vs 90.1%; p = 0.05). Men with idiopathic OA had a 15-year survivorship of 94.5% and women, 82.2% (p = 0.001); gender was not a risk factor after stratification by component size and aetiology. Using revision for excessive wear (ion levels > 7 µg/l associated with symptoms or adverse local tissue reactions) as the endpoint, the 15-year survivorship was 98.5%. Risk factors for revision for all modes of failure were an underlying pathology of hip dysplasia, a contact patch to rim (CPR) distance of 7 mm or less, an age at surgery of 55 years or less, and a femoral component size of 46 mm or less. Specific risk factors for aseptic failure of the femoral component were early surgical technique, a cementless metaphyseal stem, and a body mass index of 24 kg/m. 2. or less. Conclusion. HRA is a viable concept; metal-on-metal bearings are well suited for this procedure when a well-designed device is properly implanted. The best results were obtained in men with OA, but survivorship was better for other underlying pathologies and for women after changes were made to the technique of implantation. Lifetime durability is a possible outcome for many patients despite a high level of activity. Cite this article: Bone Joint J 2018;100-B:1424–33

Objectives. Degenerative disc disease (DDD) and osteoarthritis (OA) are relatively frequent causes of disability amongst the elderly; they constitute serious socioeconomic costs and significantly impair quality of life. Previous studies to date have found that aggrecan variable number of tandem repeats (VNTR) contributes both to DDD and OA. However, current data are not consistent across studies. The purpose of this study was to evaluate systematically the relationship between aggrecan VNTR, and DDD and/or OA. Methods. This study used a highly sensitive search strategy to identify all published studies related to the relationship between aggrecan VNTR and both DDD and OA in multiple databases from January 1996 to December 2016. All identified studies were systematically evaluated using specific inclusion and exclusion criteria. Cochrane methodology was also applied to the results of this study. Results. The final selection of seven studies was comprehensively evaluated and includes results for 2928 alleles. The most frequent allele among all the studies was allele 27. After comparing the distributions of each allele with others, statistically significant differences have been found in the distribution of the alleles by the two groups, with an over-representation of allele (A)21 (disease: 3.22%, control: 0.44%). Thus, carrying A21 increased the risk of DDD. Such an association was not found to be statistically significant when considering the risk of OA. Conclusions. The findings suggest that VNTR A21 seems to be associated with higher risk to DDD, however, such an association may not be statistically significant regarding the risk of OA. Cite this article: L. Cong, G. Tu, D. Liang. A systematic review of the relationship between the distributions of aggrecan gene VNTR polymorphism and degenerative disc disease/osteoarthritis. Bone Joint Res 2018;7:308–317. DOI: 10.1302/2046-3758.74.BJR-2017-0207.R1

Aims. There is little information about how to manage patients with a recurvatum deformity of the distal tibia and osteoarthritis (OA) of the ankle. The aim of this study was to evaluate the functional and radiological outcome of addressing this deformity using a flexion osteotomy and to assess the progression of OA after this procedure. Patients and Methods. A total of 39 patients (12 women, 27 men; mean age 47 years (28 to 72)) with a distal tibial recurvatum deformity were treated with a flexion osteotomy, between 2010 and 2015. Nine patients (23%) subsequently required conversion to either a total ankle arthroplasty (seven) or an arthrodesis (two) after a mean of 21 months (9 to 36). A total of 30 patients (77%), with a mean follow-up of 30 months (24 to 76), remained for further evaluation. Functional outcome, sagittal ankle joint OA using a modified Kellgren and Lawrence Score, tibial lateral surface (TLS) angle, and talar offset ratio (TOR) were evaluated on pre- and postoperative weight-bearing radiographs. Results. Postoperatively, the mean score for pain, using a visual analogue scale, decreased significantly from 4.3 to 2.5 points and the mean American Orthopaedic Foot & Ankle Society (AOFAS) hindfoot score improved significantly from 59 to 75 points (both p < 0.001). The mean TLS angle increased significantly by 6.6°; the mean TOR decreased significantly by 0.24 (p < 0.001). Radiological evaluation showed an improvement or no progression of sagittal ankle joint OA in 32 ankles (82%), while seven ankles (18%) showed further progression. Conclusion. A flexion osteotomy effectively improved the congruency of the ankle joint. In 30 patients (77%), the joint could be saved, whereas in nine patients (23%), the treatment delayed a joint-sacrificing procedure. Cite this article: Bone Joint J 2019;101-B:682–690

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

Objectives. Activation of the leptin pathway is closely correlated with human knee cartilage degeneration. However, the role of the long form of the leptin receptor (Ob-Rb) in cartilage degeneration needs further study. The aim of this study was to determine the effect of increasing the expression of Ob-Rb on chondrocytes using a lentiviral vector containing Ob-Rb. Methods. The medial and lateral cartilage samples of the tibial plateau from 12 osteoarthritis (OA) patients were collected. Ob-Rb messenger RNA (mRNA) was detected in these samples. The Ob-Rb-overexpressing chondrocytes and controls were treated with different doses of leptin for two days. The activation of the p53/p21 pathway and the number of senescence-associated β-galactosidase (SA-β-gal)-positive cells were evaluated. The mammalian target of rapamycin (mTOR) signalling pathway and autophagy were detected after the chondrocytes were treated with a high dose of leptin. Results. In total, 12 cases were found to have severe medial cartilage wear compared with the lateral cartilage. Immunofluorescence showed that the expression of Ob-Rb in the medial cartilage of the tibial plateau was high. High levels of leptin led to cell cycle arrest and inhibited autophagy. After overexpression of Ob-Rb, the physiological dose of leptin induced cell senescence in the chondrocytes. High doses of leptin inhibited autophagy by activating the mTOR signalling pathway. Blockade of the mTOR signalling pathway could restore autophagy and partially reverse senescence induced by leptin in chondrocytes. Conclusion. In summary, the present study demonstrated that high doses of leptin induce cell senescence by activating the mTOR pathway in chondrocytes from OA cartilage. Highly expressed Ob-Rb accelerates chondrocyte senescence by activating the leptin pathway in OA. Cite this article: X. Zhao, P. Huang, G. Li, L. Zhendong, G. Hu, Q. Xu. Activation of the leptin pathway by high expression of the long form of the leptin receptor (Ob-Rb) accelerates chondrocyte senescence in osteoarthritis. Bone Joint Res 2019;8:425–436. DOI: 10.1302/2046-3758.89.BJR-2018-0325.R2

Objectives. Salubrinal is a synthetic agent that elevates phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α) and alleviates stress to the endoplasmic reticulum. Previously, we reported that in chondrocytes, Salubrinal attenuates expression and activity of matrix metalloproteinase 13 (MMP13) through downregulating nuclear factor kappa B (NFκB) signalling. We herein examine whether Salubrinal prevents the degradation of articular cartilage in a mouse model of osteoarthritis (OA). Methods. OA was surgically induced in the left knee of female mice. Animal groups included age-matched sham control, OA placebo, and OA treated with Salubrinal or Guanabenz. Three weeks after the induction of OA, immunoblotting was performed for NFκB p65 and p-NFκB p65. At three and six weeks, the femora and tibiae were isolated and the sagittal sections were stained with Safranin O. Results. Salubrinal suppressed the progression of OA by downregulating p-NFκB p65 and MMP13. Although Guanabenz elevates the phosphorylation level of eIF2α, it did not suppress the progression of OA. Conclusions. Administration of Salubrinal has chondroprotective effects in arthritic joints. Salubrinal can be considered as a potential therapeutic agent for alleviating symptoms of OA. Cite this article: Bone Joint Res 2015;4:84–92

Objectives. The aim of this study was to identify key pathological genes in osteoarthritis (OA). Methods. We searched and downloaded mRNA expression data from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) of joint synovial tissues from OA and normal individuals. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analyses were used to assess the function of identified DEGs. The protein-protein interaction (PPI) network and transcriptional factors (TFs) regulatory network were used to further explore the function of identified DEGs. The quantitative real-time polymerase chain reaction (qRT-PCR) was applied to validate the result of bioinformatics analysis. Electronic validation was performed to verify the expression of selected DEGs. The diagnosis value of identified DEGs was accessed by receiver operating characteristic (ROC) analysis. Results. A total of 1085 DEGs were identified. KEGG pathway analysis displayed that Wnt was a significantly enriched signalling pathway. Some hub genes with high interactions such as USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, and ZNF423 were identified in the PPI and TFs network. The results of qRT-PCR showed that GADD45B, ADAMTS1, and TFAM were down-regulated in joint synovial tissues of OA, which was consistent with the bioinformatics analysis. The expression levels of USP46, CPVL, FOSL2, and PTGS1 in electronic validation were compatible with the bio-informatics result. CPVL and TFAM had a potential diagnostic value for OA based on the ROC analysis. Conclusion. The deregulated genes including USP46, CPVL, FKBP5, FOSL2, GADD45B, PTGS1, ZNF423, ADAMTS1, and TFAM might be involved in the pathology of OA. Cite this article: X. Zhang, Y. Bu, B. Zhu, Q. Zhao, Z. Lv, B. Li, J. Liu. Global transcriptome analysis to identify critical genes involved in the pathology of osteoarthritis. Bone Joint Res 2018;7:298–307. DOI: 10.1302/2046-3758.74.BJR-2017-0245.R1

Objectives. This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model. Methods. Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1β), and gene expression changes were examined by real-time polymerase chain reaction (PCR). Results. The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1β, while also reducing the induction of MMP-13 by IL-1β in vitro. Conclusion. The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA. Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Joint Res 2018;7:252–262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1

Aims. Patients may present with concurrent symptomatic osteoarthritis (OA) of the hip and degenerative disorders of the lumbar spine, with surgical treatment being indicated for both. Whether arthroplasty of the hip or spinal surgery should be performed first remains uncertain. Materials and Methods. Clinical scenarios were devised for a survey asking the preferred order of surgery and the rationale for this decision for five fictional patients with both OA of the hip and degenerative lumbar disorders. These were symptomatic OA of the hip and: 1) lumbar spinal stenosis with neurological claudication; 2) lumbar degenerative spondylolisthesis with leg pain; 3) lumbar disc herniation with leg weakness; 4) lumbar scoliosis with back pain; and 5) thoracolumbar disc herniation with myelopathy. This survey was sent to 110 members of The Hip Society and 101 members of the Scoliosis Research Society. The choices of the surgeons were compared among scenarios and between surgical specialties using the chi-squared test. The free-text comments were analyzed using text-mining. Results. Responses were received from 51 hip surgeons (46%) and 37 spine surgeons (37%). The percentages of hip surgeons recommending ‘hip first’ differed significantly among scenarios: 59% for scenario 1; 73% for scenario 2; 47% for scenario 3; 47% for scenario 4; and 10% for scenario 5 (p < 0.001). The percentages of spine surgeons recommending ‘hip first’ were 49% for scenario 1; 70% for scenario 2; 19% for scenario 3; 78% for scenario 4; and 0% for scenario 5. There were significant differences between the groups for scenarios 3 (more hip surgeons recommended ‘hip first’; p = 0.012) and 4 (more hip surgeons recommended ‘spine first’; p = 0.006). Conclusion. In patients with coexistent OA of the hip and degenerative disorders of the spine, the question of ‘hip or spinal surgery first’ elicits relatively consistent answers in some clinical scenarios, but remains controversial in others, even for experienced surgeons. The nature of neurological symptoms can influence surgeons’ decision-making. Cite this article: Bone Joint J 2019;101-B(6 Supple B):37–44

Objectives. Osteoarthritis (OA) is the most common form of arthritis, affecting approximately 15% of the human population. Recently, increased concentration of nitric oxide in serum and synovial fluid in patients with OA has been observed. However, the exact role of nitric oxide in the initiation of OA has not been elucidated. The aim of the present study was to investigate the role of nitric oxide in innate immune regulation during OA initiation in rats. Methods. Rat OA was induced by performing meniscectomy surgery while cartilage samples were collected 0, 7, and 14 days after surgery. Cartilage cytokine levels were determined by using enzyme-linked immunosorbent assay, while other proteins were assessed by using Western blot. Results. In the time course of the study, nitric oxide was increased seven and 14 days after OA induction. Pro-inflammatory cytokines including tumour necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were decreased. L-NG-Nitroarginine methyl ester (L-NAME, a non-specific nitric oxide synthase inhibitor) significantly decreased cartilage nitric oxide and blocked immune suppression. Further, L-NAME decreased Matrix metalloproteinase (MMPs) and increased tissue inhibitor of metalloproteinase (TIMP) expression in meniscectomised rats. Conclusion. Nitric oxide-dependent innate immune suppression protects cartilage from damage in the early stages of OA initiation in rats. Cite this article: C-C. Hsu, C-L. Lin, I-M. Jou, P-H. Wang, J-S. Lee. The protective role of nitric oxide-dependent innate immunosuppression in the early stage of cartilage damage in rats: Role of nitric oxide in ca rtilage da mage. Bone Joint Res 2017;6:253–258. DOI: 10.1302/2046-3758.64.BJJ-2016-0161.R1

Aims. The modified Dunn procedure has the potential to restore the anatomy in hips with severe slipped capital femoral epiphyses (SCFE). However, there is a risk of developing avascular necrosis of the femoral head (AVN). In this paper, we report on clinical outcome, radiological outcome, AVN rate and complications, and the cumulative survivorship at long-term follow-up in patients undergoing the modified Dunn procedure for severe SCFE. Patients and Methods. We performed a retrospective analysis involving 46 hips in 46 patients treated with a modified Dunn procedure for severe SCFE (slip angle > 60°) between 1999 and 2016. At nine-year-follow-up, 40 hips were available for clinical and radiological examination. Mean preoperative age was 13 years, and 14 hips (30%) presented with unstable slips. Mean preoperative slip angle was 64°. Kaplan–Meier survivorship was calculated. Results. At the latest follow-up, the mean Merle d’Aubigné and Postel score was 17 points (14 to 18), mean modified Harris Hip Score was 94 points (66 to 100), and mean Hip Disability and Osteoarthritis Outcome Score was 91 points (67 to 100). Postoperative slip angle was 7° (1° to 16°). One hip (2%) had progression of osteoarthritis (OA). Two hips (5%) developed AVN of the femoral head and required further surgery. Three other hips (7%) underwent implant revision due to screw breakage or change of wires. Cumulative survivorship was 86% at ten-year follow-up. Conclusion. The modified Dunn procedure for severe SCFE resulted in a low rate of AVN, low risk of progression to OA, and high functional scores at long-term follow-up. The slip deformities were mainly corrected but secondary impingement deformities can develop in some hips and may require further surgical treatment. Cite this article: Bone Joint J 2019;101-B:403–414

Objectives. Intra-articular injections of local anaesthetics (LA), glucocorticoids (GC), or hyaluronic acid (HA) are used to treat osteoarthritis (OA). Contrast agents (CA) are needed to prove successful intra-articular injection or aspiration, or to visualize articular structures dynamically during fluoroscopy. Tranexamic acid (TA) is used to control haemostasis and prevent excessive intra-articular bleeding. Despite their common usage, little is known about the cytotoxicity of common drugs injected into joints. Thus, the aim of our study was to investigate the effects of LA, GC, HA, CA, and TA on the viability of primary human chondrocytes and tenocytes in vitro. Methods. Human chondrocytes and tenocytes were cultured in a medium with three different drug dilutions (1:2; 1:10; 1:100). The following drugs were used to investigate cytotoxicity: lidocaine hydrochloride 1%; bupivacaine 0.5%; triamcinolone acetonide; dexamethasone 21-palmitate; TA; iodine contrast media; HA; and distilled water. Normal saline served as a control. After an incubation period of 24 hours, cell numbers and morphology were assessed. Results. Using LA or GC, especially triamcinolone acetonide, a dilution of 1:100 resulted in only a moderate reduction of viability, while a dilution of 1:10 showed significantly fewer cell counts. TA and CA reduced viability significantly at a dilution of 1:2. Higher dilutions did not affect viability. Notably, HA showed no effects of cytotoxicity in all drug dilutions. Conclusion. The toxicity of common intra-articular injectable drugs, assessed by cell viability, is mainly dependent on the dilution of the drug being tested. LA are particularly toxic, whereas HA did not affect cell viability. Cite this article: P. Busse, C. Vater, M. Stiehler, J. Nowotny, P. Kasten, H. Bretschneider, S. B. Goodman, M. Gelinsky, S. Zwingenberger. Cytotoxicity of drugs injected into joints in orthopaedics. Bone Joint Res 2019;8:41–48. DOI: 10.1302/2046-3758.82.BJR-2018-0099.R1

Aims. Tibiotalocalcaneal (TTC) fusion is used to treat a variety of conditions affecting the ankle and subtalar joint, including osteoarthritis (OA), Charcot arthropathy, avascular necrosis (AVN) of the talus, failed total ankle arthroplasty, and severe deformity. The prevalence of postoperative complications remains high due to the complexity of hindfoot disease seen in these patients. The aim of this study was to analyze the relationship between preoperative conditions and postoperative complications in order to predict the outcome following primary TTC fusion. Methods. We retrospectively reviewed the medical records of 101 patients who underwent TTC fusion at the same institution between 2011 and 2019. Risk ratios (RRs) associated with age, sex, diabetes, cardiovascular disease, smoking, preoperative ankle deformity, and the use of bone graft during surgery were related to the postoperative complications. We determined from these data which pre- and perioperative factors significantly affected the outcome. Results. Out of the 101 patients included in the study, 29 (28.7%) had nonunion, five (4.9%) required below-knee amputation (BKA), 40 (39.6%) returned to the operating theatre, 16 (15.8%) had hardware failure, and 22 (21.8%) had a postoperative infection. Patients with a preoperative diagnosis of Charcot arthropathy and non-traumatic OA had significantly higher nonunion rates of 44.4% (12 patients) and 39.1% (18 patients) (p = 0.016) and infection rates of 29.6% (eight patients) and 37% (17 patients) compared to patients with traumatic arthritis, respectively (p = 0.002). There was a significantly increased rate of nonunion in diabetic patients (RR 2.22; p = 0.010). Patients with chronic kidney disease were 2.37-times more likely to have a nonunion (p = 0.006). Patients aged over 60 years had more than a three-fold increase in the rate of postoperative infection (RR 3.60; p = 0.006). The use of bone graft appeared to be significantly protective against postoperative infection (p = 0.019). Conclusion. We were able to confirm, in the largest series of TTC ankle fusions currently in the literature, that there remains a high rate of complications following this procedure. We found that patients with a Charcot or non-traumatic arthropathy had an increased risk of nonunion and postoperative infection compared to individuals with traumatic arthritis. Those with diabetes, chronic kidney disease, or aged over 60 years had an increased risk of nonunion. These findings help to confirm those of previous studies. Additionally, our study adds to the literature by showing that autologous bone graft may help in decreasing infection rates. These data can be useful to surgeons and patients when considering, discussing and planning TTC fusion. It helps surgeons further understand which patients are at a higher risk for postoperative complications when undergoing TTC fusion. Cite this article: Bone Joint J. 2020;102-B(3):345–351