It is probable that both genetic and environmental factors play some part in the aetiology of most cases of degenerative hip disease. Geneticists have identified some single gene disorders of the hip, but have had difficulty in identifying the genetics of many of the common causes of degenerative hip disease. The heterogeneity of the phenotypes studied is part of the problem. A detailed classification of phenotypes is proposed. This study is based on careful documentation of 2003 consecutive total hip replacements performed by a single surgeon between 1972 and 2000. The concept that developmental problems may initiate degenerative hip disease is supported. The influences of gender, age and body mass index are outlined. Biomechanical explanations for some of the radiological appearances encountered are suggested. The body weight lever, which is larger than the abductor lever, causes the abductor power to be more important than body weight. The possibility that a deficiency in joint lubrication is a cause of degenerative hip disease is discussed. Identifying the phenotypes may help geneticists to identify genes responsible for degenerative hip disease, and eventually lead to a definitive classification.

Introduction and aims: Familial aggregation of low back pain (LBP) symptoms has been described. However, this may be due to genetic factors or common exposure to environmental factors. This study evaluated the relative contribution of genetic and environmental factors to childhood LBP. Methods: Data was collected from 1995 to 1998 from a national sample of 1790 Finnish twins aged 11-years. A validated pain questionnaire was used to assess LBP pain. Information was also collected on children’s perception of parent-child relationships, parenting behaviours and home environment. In addition, children were asked about various sedentary and active life-style activities. Variance components for genetic and environmental factors were estimated by using biometric structural equation modelling techniques. Results: The prevalence of LBP at least once a month was 15.7%, and at least once a week was 6.7%. There was small difference in pairwise similarity of LBP between monozygotic and dizygotic pairs, suggesting little genetic influence. LBP was not associated with either sedentary or active lifestyle activities, but was strongly associated with children’s unsatisfactory perception of the following: home environment (p< 0.001), parenting behaviours (Spearman rho = 0.12, 95% CI 0.06–0.18), relationship with mother (p=0.02) and father (p=0.04). Of the total variance in LBP, 41% (95% CI 34 to 48) could be attributed to shared environmental factors within families; and 59% (52 to 66) to unshared environmental factors. Conclusion: Genetic factors seem to play a very minor role in LBP in 11-year-old twins. Rather than being related to various aspects of lifestyle activities, childhood LBP is best predicted by children’s perception of home environment and family functioning

Osteoporosis (OP) is a chronic metabolic bone disease characterized by the decrease of bone tissue per unit volume under the combined action of genetic and environmental factors, which leads to the decrease of bone strength, makes the bone brittle, and raises the possibility of bone fracture. However, the exact mechanism that determines the progression of OP remains to be underlined. There are hundreds of trillions of symbiotic bacteria living in the human gut, which have a mutually beneficial symbiotic relationship with the human body that helps to maintain human health. With the development of modern high-throughput sequencing (HTS) platforms, there has been growing evidence that the gut microbiome may play an important role in the programming of bone metabolism. In the present review, we discuss the potential mechanisms of the gut microbiome in the development of OP, such as alterations of bone metabolism, bone mineral absorption, and immune regulation. The potential of gut microbiome-targeted strategies in the prevention and treatment of OP was also evaluated. Cite this article: Bone Joint Res 2020;9(8):524–530

Adolescent idiopathic scoliosis (AIS), defined by an age at presentation of 11 to 18 years, has a prevalence of 0.47% and accounts for approximately 90% of all cases of idiopathic scoliosis. Despite decades of research, the exact aetiology of AIS remains unknown. It is becoming evident that it is the result of a complex interplay of genetic, internal, and environmental factors. It has been hypothesized that genetic variants act as the initial trigger that allow epigenetic factors to propagate AIS, which could also explain the wide phenotypic variation in the presentation of the disorder. A better understanding of the underlying aetiological mechanisms could help to establish the diagnosis earlier and allow a more accurate prediction of deformity progression. This, in turn, would prompt imaging and therapeutic intervention at the appropriate time, thereby achieving the best clinical outcome for this group of patients. Cite this article: Bone Joint J 2022;104-B(8):915–921

Aim. Osteoarthritis (OA) is caused by complex interactions between genetic and environmental factors. Epigenetic mechanisms control the expression of genes and are likely to regulate the OA transcriptome. We performed integrative genomic analyses to define methylation-gene expression relationships in osteoarthritic cartilage. Patients and Methods. Genome-wide DNA methylation profiling of articular cartilage from five patients with OA of the knee and five healthy controls was conducted using the Illumina Infinium HumanMethylation450 BeadChip (Illumina, San Diego, California). Other independent genome-wide mRNA expression profiles of articular cartilage from three patients with OA and three healthy controls were obtained from the Gene Expression Omnibus (GEO) database. Integrative pathway enrichment analysis of DNA methylation and mRNA expression profiles was performed using integrated analysis of cross-platform microarray and pathway software. Gene ontology (GO) analysis was conducted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Results. We identified 1265 differentially methylated genes, of which 145 are associated with significant changes in gene expression, such as DLX5, NCOR2 and AXIN2 (all p-values of both DNA methylation and mRNA expression < 0.05). Pathway enrichment analysis identified 26 OA-associated pathways, such as mitogen-activated protein kinase (MAPK) signalling pathway (p = 6.25 × 10-4), phosphatidylinositol (PI) signalling system (p = 4.38 × 10-3), hypoxia-inducible factor 1 (HIF-1) signalling pathway (p = 8.63 × 10-3 pantothenate and coenzyme A (CoA) biosynthesis (p = 0.017), ErbB signalling pathway (p = 0.024), inositol phosphate (IP) metabolism (p = 0.025), and calcium signalling pathway (p = 0.032). Conclusion. We identified a group of genes and biological pathwayswhich were significantly different in both DNA methylation and mRNA expression profiles between patients with OA and controls. These results may provide new clues for clarifying the mechanisms involved in the development of OA. Cite this article: A. He, Y. Ning, Y. Wen, Y. Cai, K. Xu, Y. Cai, J. Han, L. Liu, Y. Du, X. Liang, P. Li, Q. Fan, J. Hao, X. Wang, X. Guo, T. Ma, F. Zhang. Use of integrative epigenetic and mRNA expression analyses to identify significantly changed genes and functional pathways in osteoarthritic cartilage. Bone Joint Res 2018;7:343–350. DOI: 10.1302/2046-3758.75.BJR-2017-0284.R1

Background. The factors influencing normal spine curvature in midlife are unknown. We performed an MR and plain radiograph study on well characterised, unselected twin volunteers from the TwinsUK register (. www.twinsuk.ac.uk. ) to determine the relative contributions of genetic and environmental factors to spine curve. Methods. T2 weighted MR scans and long spine standing radiographs were obtained at the same morning visit on twin pairs. Midline sagittal MR images were coded for 4 degenerative features. SpineviewTM software was applied plain films and calculated the angles of curvature. A classical twin study was performed. Multivariate regression analysis was used to determine the association between spine curves, LDD and confounders (age, body mass index). Results. Data were available on 110 monozygotic (MZ) and 136 dizygotic (DZ) female twins. Mean age was 64.3 years (range 40.1–79.3); age was associated with increasing lumbar lordosis (p=0.02). The AE model (comprising additive genetic and unique environmental factors) was the most suitable model for both lumbar lordosis and thoracic kyphosis (as determined by Akaike information criterion). Heritability estimates = 59% (42–71%) for lumbar lordosis; and 61% (46–74%) for thoracic kyphosis. After adjusting for age and BMI, lumbar lordosis was significantly associated with a number of features of LDD (p<0.001) including disc signal intensity and osteophytes. Conclusion. The twins are known to be representative of women in the general population. Lumbar lordosis and thoracic kyphosis of the spine have considerable heritable component in females suggesting that a search for individual gene variants would be a reasonable next step. This abstract was presented at 14th Congress of the International Society for Twin Studies. Conflicts of interest: No conflicts of interest. Sources of funding: No funding obtained

Background: Congenital talipes equinovarus (CTEV) is a common developmental disorder of the foot, affecting between 1 and 4.5 babies per 1000 live births. The etiology is not well elucidated. While both genetic and environmental factors are implicated, no specific genes have been identified and little is known about environmental risk factors. Methods: We conducted a case-control study of idiopathic congenital talipes equinovarus (ICTEV) in the United Kingdom. 194 cases and 60 controls were recruited. Pedigrees were obtained for 162 cases. Results: The rank of the index pregnancy, maternal education and cesarean delivery were significantly associated with ICTEV risk in a multivariate model. There were suggestions that maternal use of folic acid supplements in the three months before the pregnancy decreased ICTEV risk, and that parental smoking during the pregnancy increased risk. One quarter of pedigrees showed a family history of CTEV, and autosomal dominant inheritance was suggested in some of these. Conclusion: Uterine restriction did not appear to have a strong influence on ICTEV development in our study. Large population-based studies are needed to clarify the etiology of this common developmental disorder

The significance of flat-foot in childhood and adolescence in Italy has never been studied on a statistically significant sample. In our survey, thousands of subjects from different regions of northern, central and southern Italy (Calabria, Lazio, Umbria, Lombardia) were studied in order to determine the prevalence of flat-foot and search for possible genetic or environmental factors that may influence the normal development of the longitudinal arch, starting from birth. Materials and methods: In order to obtain the footprints of children (aged 6–11, attending primary school), we used a polarized light podoscope; we used this instrument, instead of more advanced ones such as baropodometric platforms, because flat-foot diagnosis is basically static and also because the majority of existing studies use the same methodology and have established simple, reliable and reproducible diagnostic criteria, making a more accurate data comparison possible. Podoscopy was integrated with anamnesis, physical examination and measurement of weight and height. Footprint morphology has been related with variables such as age, sex, geographical area of origin and BMI (Body Mass Index)

Introduction: Between 1 and 4 per 1000 births worldwide are affected by clubfoot. Clubfoot etiology is unclear, but both genetic and environmental factors are thought to be involved. Low folate status in pregnant women has been implicated in several congenital malformations and folate metabolism may be affected by polymorphisms in the MTHFR gene. Methods: Using a case-parent triad design, we investigated whether the MTHFR C677T polymorphism, and maternal peri-conceptional folic acid supplement use, influenced risk of isolated clubfoot. 375 case-parent triads took part. Results: Among children there was a significant trend of decreasing clubfoot risk with increasing number of Talleles: relative risk (RR ) CT vs CC=0.75 (95% CI: 0.57,0.97); RR TT vs CC=0.57 (95% CI: 0.37,0.91); p trend=0.006. This association was not modified by maternal folic acid use. Conclusion: Maternal MTHFR genotype did not influence risk of clubfoot in the offspring overall, although a possible interaction with folic acid use was found. This is the first report of a specific genetic polymorphism associated with clubfoot. The direction of the association is intriguing and suggests DNA synthesis may be relevant in clubfoot development. However, clubfoot mechanisms are poorly understood and the folate metabolism pathway is complex. Further research is needed to elucidate these relationships

Introduction: Bone phenotype, such as osteoarthritis (OA) pattern and development of osteolysis or heterotopic ossification (HO) after THA, may be governed by genetic and environmental factors. We investigated whether single nucleotide polymorphisms within the gene encoding secreted-Frizzled Related Protein-3, FRZB Arg200Trp and FRZB Arg324Gly influence bone phenotype. Methods: Genomic DNA was extracted from 609 subjects at a mean of 11 years following cemented THA for idiopathic osteoarthritis. Pre-operative OA was defined using The American College of Rheumatology criteria and post operative HO after primary THA was assessed using Brooker’s classification. Results: For FRZB Arg200Trp, minor allele carriage (MAC) was greater in subjects with pre-operative pelvic osteophytes (n=267) versus those without osteophytes (n=34) (MAC 27.9% versus 6.3%, Fisher’s exact test p=0.037). There were no associations with other radiographic criteria of OA. MAC was also higher in HO+ve subjects (n=291) versus HO-ve subjects (n=341), (MAC 21.7% versus 12.0%, χ. 2. test p=0.063). Finally MAC was 14.2% in osteolysis +ve subjects (n=268) and 21.7% in osteolysis –ve subjects (n=341) (χ. 2. test p=0.041). The adjusted odds ratios for pelvic osteophytes and HO with carriage of the rare FRZB 200 variant were 4.34 (1.01–18.7 p=0.048) and 1.64 (1.05 to 2.54, p=0.028) respectively. The adjusted odds ratio for osteolysis was 0.62 (0.38 to 0.99 p=0.049). There were no bone phenotype associations with the FRZB Arg324Gly variants. Discussion: Carriage of the FRZB 200Trp allele is positively associated with osteophyte and HO formation and negatively associated with osteolysis, suggesting this locus may be a marker for pro-osteoblastic activity

1 . The magnitude of the problem of congenital anomalies becomes evident when one takes into consideration the fact that they cause the death of approximately one quarter of the human race either before or shortly after birth, and handicap an appreciable proportion of the survivors throughout their lives. Further, a significant percentage of infants judged to be normal at birth are found in later life to suffer from "disguised" anomalies of the skeleton and soft tissues. Though the study of genetic factors leading to congenital defects has attracted a great deal of attention during the last few decades, the importance of environmental causes of human malformations has received relatively less emphasis. The association of congenital anomalies such as cataract and cardiac septal defects with maternal intercurrent infection of rubella during the early months of pregnancy demonstrates clearly that changes in the germplasm cannot always be invoked as the cause of developmental abnormalities. Congenital malformations that are sometimes genetically determined, such as microphthalmos, cleft palate, and certain skeletal abnormalities, can be caused in the offspring not only by maternal nutritional deficiencies and x-radiation but also, at least in some animals, such as chickens, rats and rabbits, by the introduction of certain substances like insulin into the environment of the embryo during its development. 2. Since very little is known of the detailed histology of the early human embryo, the histological examination of cases of perverted growth is mainly limited to aborted foetuses which, unfortunately, tend to present varying degrees of post-mortem degeneration before accurate histological methods can be applied. It is exactly in this field that animal experiments can offer valuable help. According to Mall and other embryologists the pathological changes that take place in human foetuses and those obtained experimentally in animals are not merely "analogous or similar but identical.". 3. An attempt has been made to review, in some detail, the more important work which has been carried out on experimental teratogenesis, on the epidemiological implications of developmental arrests in humans, and on foetal abnormalities associated with maternal metabolic and hormonal disorders during pregnancy. 4. The technique employed for injection of insulin into the egg yolk has been described. Methods used for the estimation of blood sugar in chick embryos at various stages after injection of insulin and special histochemical techniques for localising polysaccharides in cartilage have been outlined. 5. A few salient experimental results have been tabulated, and some of the insulin-induced abnormalities have been illustrated. 6. The possible mechanism of action of insulin in the causation of the various developmental anomalies has been discussed. Broadly speaking, insulin seems to affect primarily the part or tissue which is in the most active stage of growth or differentiation at the time of the injection. Within the range of 0·05 to 6 units of insulin employed, the incidence, severity and distribution of the deformities appear to increase with the dose of the hormone. It has been observed that the hypoglycaemia caused by insulin injection is not counteracted till about the twelfth day of incubation, presumably because of excessive accumulation of glycogen in the yolk-sac membrane immediately after the injection, and because of lack of glycogen storage in the embryonic liver and the absence of active secretion in the endocrine glands concerned with the carbohydrate metabolism of the embryo. It has been suggested that this unchecked hypoglycaemia may deprive the mesenchyme, pre-cartilage and cartilage of glycogen and mucopolysaccharides (chondroiten-sulphuric acid complexes), depending on the time of injection and the dose of insulin, and thus not only give rise to a variety of single and multiple deformities in the cartilaginous skeleton but also interfere with the normal endochondral ossification, resulting in a generalised developmental disturbance of bone resembling osteogenesis imperfecta in the human. 7. Insulin-induced abnormalities can be prevented to a remarkable extent by injecting nicotinamide and riboflavin into eggs along with insulin. 8. The question of the practical application of the knowledge gained from experimental observations on insulin-induced developmental abnormalities in explaining the possible causation of congenital anomalies in humans by genetic and environmental teratogenic factors, has been discussed. It is suggested that the orderly progression from the mesenchymatous condensation to cartilage, and then through calcified cartilage to bone, may be disturbed by these teratogenic factors at critical phases during the development of the embryo, and a variety of single and multiple skeletal deformities may thus be induced. 9. A plea is made for routine pathological and radiological examination of aborted foetuses and stillborn infants more or less on the lines followed for experimentally induced deformities with a view to applying the knowledge gained from animal experiments to a better understanding of the etiology and pathology of human congenital anomalies. 10. As regards the possible prevention of these deformities, it is not always easy to offer sound eugenic advice in the cases of congenital malformations determined partly or completely by genetic factors, for two important reasons. First, it is often difficult to distinguish between genetically determined congenital anomalies and their phenocopies. Secondly, genetically determined developmental defects sometimes show surprisingly variable expressivity and penetrance. For the conditions in which both genetic and environmental factors are involved, the most profitable immediate line of attack would be on the environmental factors. A relatively simpler problem is presented by the malformations which are, for all practical purposes, entirely caused by environmental factors. Measures to prevent congenital anomalies caused by prenatal rubella, such as exposure of girls to the disease during childhood and protection of pregnant women during the early stages of pregnancy by immune serum, are under active consideration. 11 . Further energetic investigation of the causes of permaturity, stillbirths, monstrosities and congenital malformations is urgently needed, before embarking on a successful programme for prevention. "The day of successful prophylaxis is not yet, but it is much nearer than seemed possible a few years ago."

The side distribution of single spinal curves in our school screening referrals for 1988–99 (n=218) suggests that the mechanism(s) determining curve laterality for the upper spine differs from those for the lower spine. We address here the laterality of right thoracic AIS. In the search to understand the aetiology of AIS some workers focus on mechanisms initiated in embryonic life including a disturbance of bilateral symmetry. The normal external bilateral symmetry of the body, highly conserved in vertebrates, results from a default process involving mesodermal somites. The normal internal asymmetry of the heart, major blood vessels, lungs and gut with its glands is also highly conserved among vertebrates. There is recent evidence that vertebrates retain an archaic asymmetric visceral organization in thoracic and abdominal organs (Cooke). In early embryonic life the visceral asymmetry develops from the breaking of the initial bilateral symmetry by a binary asymmetry switch producing asymmetric gene expression around the embryonic node and/or in the lateral plate mesoderm. In the mouse this switch occurs during gastrulation by cilia driving a leftward flow of fluid and morphogen(s) at the embryonic node (nodal flow) favouring precursors of heart, great vessels and viscera on the left. Based on the non-random laterality of thoracic AIS curves, we suggest that the binary asymmetry switch – through genetic/environmental factors extending to involve anomalously left-sided mesodermal precursors of vertebrae, ribs and/or muscles (positively or negatively), explains the distribution of right/left thoracic AIS. Some support for this hypothesis is the prevalence of scoliosis curve laterality associated with situs inversus

Aims

We aimed to develop a gene signature that predicts the occurrence of postmenopausal osteoporosis (PMOP) by studying its genetic mechanism.

Aims

Despite the interest in the association of gut microbiota with bone health, limited population-based studies of gut microbiota and bone mineral density (BMD) have been made. Our aim is to explore the possible association between gut microbiota and BMD.

Knee osteoarthritis (OA) is a major cause of pain and disability in elder people. The prevalence of radiographic OA in a population aged 35–74 years is 5–15% and about one third of involved people complain of symptoms. In the „Ulm Osteoarthritis Study“ patients undergoing total knee replacement reported a mean duration of knee pain of 10 years prior to surgery. Multiple genetic, constitutional and environmental factors contribute to the development of OA. Initial cartilage degradation leads to joint space narrowing and early osteophyte formation which can be observed radiographically. Whether elevated subchondral bone mineral density is contributing to manifestation of the disease or just a secondary reaction process is still under debate. OA finally involves not only cartilage and subchondral bone but also soft tissues in and around the joint (synovial membrane, ligaments and muscles), which often results in painful effusions, muscular shortening and stiffness. Many conservative treatment options have been developed in the past to relief these symptoms and to slow down or even stop the cartilage degradation process. Evidence to support the effectiveness of individual treatments, however, is variable. Recently the EULAR Committee for Clinical Trials determined an approach for the development of evidence based guidelines for conservative treatment of knee OA (. Pendleton et al, . Ann Rheum Dis. 2000. ;. 59. :. 936. –944. ). Through a process of quality assessment of available publications and determination of expert consensus employing a Delphi approach propositions relating to a rationale conservative management could be made:. Treatment of knee OA must be tailored to individual patients, taking into account factors such as age, comorbidity and the presence of inflammation. Optimal management requires a combination of non-pharmacological treatment modalities (regular education, exercise, appliances and weight reduction) and pharmacological approaches. Paracetamol generally is the preferred analgesic and there is enough evidence to support its application, as the pain controlling effects are comparable to NSAIDS and long term application is safe enough. NSAIDS (oral or even topical) can be considered in patients with effusion. Although some studies found NSAIDS to have better efficacy than paracetamol in the treatment of painful knee OA, the gastrointestinal side effects limit their long-term application. Therefore most experts consider their application only in patients unresponsive to paracetamol and in major effusions. In such situations long-acting steroids can be injected intra-articularly as well. While the effects of steroids in knee OA have been assessed in a number of studies, the predictors of response are still somewhat unclear and further investigations are necessary. Recent data seems to support the theory that some symptomatic slow acting drugs (glucosamine sulfate, chondroitin sulfate, diacerein and hyaluronic acid) may possess structure modifying properties. Further studies, however, are necessary to determine the pharmacoeconomic aspects of that treatment and to define the indications more precisely. Education should be an integral part in the management of knee OA. Several large randomised controlled trials have shown benefits of different educational techniques in reducing pain and increasing coping skills. Function can reliably be improved by quadriceps strengthening exercises and there is enough evidence to show the positive effects of weight reduction on the progression of the disease process. In conclusion, evidence based guidelines in the conservative management of knee OA exist. Orthopaedic Surgeons should have knowledge of the various approaches and be aware of the fact that certain clinical propositions are supported by substantial research based evidence, while others are not

Aims

Rheumatoid arthritis (RA) is a systematic autoimmune disorder, characterized by synovial inflammation, bone and cartilage destruction, and disease involvement in multiple organs. Although numerous drugs are employed in RA treatment, some respond little and suffer from severe side effects. This study aimed to screen the candidate therapeutic targets and promising drugs in a novel method.

Aims

Although knee osteoarthritis (OA) is diagnosed and monitored radiologically, actual full-thickness cartilage loss (FTCL) has rarely been correlated with radiological classification. This study aims to analyze which classification system correlates best with FTCL and to assess their reliability.

Objectives

The objective of this study was to investigate the association of four single-nucleotide polymorphisms (SNPs) of the cannabinoid receptor 2 (CNR2) gene, gene-obesity interaction, and haplotype combination with osteoporosis (OP) susceptibility.