RNA-Seq or whole transcriptome shotgun sequencing has been adopted in the last years as a reference technique to determine the presence and the quantity of different species of RNA in determined biological samples, thanks to it allows the identification every single RNA species transcribed from a reference genome. Meta-profiling takes advantage of the public availability of an increasing set of RNA-Seq data produced by different laboratories to summarize the expression levels of the different RNA species of many samples according to their biological context, giving the opportunity to perform comparisons on the gene expression profiles of different tissues by integrating data derived from a high number of studies. By using Genevestigator™; a platform which integrates RNA-Seq data into meta-profiles, we have performed a comparison between the gene expression profiles of bone, cartilage, muscle tendon and skin by means of interrogating its database with different gene sets and families with relevance to the function of the tissues of the musculoskeletal system. The collagen gene family and genes coding for proteoglycans, matrix metalloproteinases and tissue inhibitors of metalloproteinases, mechanotransduction-related proteins and signalling pathways involved in tissue development and differentiation have been analysed. Hierarchical clustering for every gene set was performed for the understanding the differences and similarities between the different tissues included in the analyses. The results of this study will help to improve our understanding of the musculoskeletal system, and will help to identify new biomarkers and signalling pathways of specific relevance for the bone, cartilage, muscle and tendon

Imaging of the musculoskeletal system is vital for delivering optimum treatment particularly in the assessment of fracture healing. X-ray and CT are adequate imaging methods for bone but, soft tissue needs other modalities such as MRI and Ultrasound. We propose the use of Freehand 3D Ultrasound to study the early stages of fracture healing by imaging the bone surfaces around the fracture site and monitoring changes in the surrounding soft tissue. Freehand 3D ultrasound is acquired by attaching a position sensor to the probe of a conventional 2D diagnostic ultrasound machine. As the probe is moved, its position and orientation are recorded along with the 2D ultrasound images. This enables slices through the body to be viewed that would be inaccessible using a normal ultrasound system. Bone surfaces around a fracture site are scanned and the data reconstructed using the Stradx and Stradwin software developed by Cambridge University, to give a 3D visualization of the area. To assess the feasibility of this proposed method the lower limbs of healthy volunteers were scanned using a 5–10MHz ultrasound probe. The scanning resolution of the system was evaluated using a phantom to ensure millimetre detail could be detected as would be required for imaging early fracture healing. It was found that detail down to 0.8mm could easily be resolved for measurement. The 3D system could accurately profile the different soft tissue interfaces. The visible surfaces of the tibia were reconstructed to give 3D models. Additional layers of soft tissue interfaces could easily be added to these models to provide more detail. This imaging modality can provided detailed 3D models of bone the bone surface and surrounding soft tissue. As ultrasound is non-ionizing, rescanning can be conducted more frequently than with CT or x-ray thus offering a more accurate assessment of a patient’s response to healing

Osteoarthritis is the most prevalent joint disease, causing severe pain, deformity and a loss of mobility. Low back pain (LBP), frequently associated with degeneration of the intervertebral disc (IVD), is the No.1 cause of Years Lived with Disability. Age is a major risk factor for both conditions. However, the reasons why susceptibility to these conditions increases with age are poorly understood. The circadian (24 hourly) clocks in the brain and periphery direct key aspects of physiology through rhythmic control of tissue-specific sets of downstream genes. Work from our group focuses on the roles of circadian clocks in the articular cartilage and IVD. We show that the daily rhythm in these tissues becomes dampened and out-of-phase during ageing. Further, our data identify circadian clock disruption in cartilage and IVD as a new target of inflammation. Moreover, we show that mice with targeted knockout of an essential clock gene (BMAL1) in chondrocytes and disc cells have profound, yet tissue-specific degeneration in the articular cartilage and IVD. These findings implicate the local skeletal clock as a key regulatory mechanism for tissue homeostasis. This new avenue of research holds potential to better understand, and eventually treat these debilitating conditions.

X-ray is the standard method for monitoring fracture healing however it is not ideal; signs of healing are not normally visible on X-ray until around 6–8 weeks post fracture. Ultrasonography allows the detection of both the initial haematoma, usually formed immediately after fracture, and the small calcium deposits laid down between broken bone ends in the first stages of fracture healing. It has been reported that these early indicators of the healing process are visible as early as 1–2 weeks after fracture. We use Freehand 3D Ultrasound to monitor the early stages of fracture healing as both the bone surface and surrounding soft tissues can be imaged simultaneously.

The Freehand 3D Ultrasound system consists of a standard Ultrasound machine, a PC running STRAD-WIN (Medical Imaging Group, Cambridge University) 3D software, and an optical tracking devise (NDI Polaris) to record the position and orientation of the Ultrasound probe during scanning. Images are transferred from the Ultrasound machine to the PC using RF capture through out a scan. Calibrating the system matches up the correct image with the correct probe position to produce a 3D dataset.

We segment features of interest on the sequence of 2D images to construct a 3D model. These models are rotatable and provide views of the scanned anatomy that are not otherwise achievable using conventional Ultrasound or X-ray. The 3D data set can also be resliced through any plane to provide further views.

To conduct a 3D Ultrasound scan takes the same amount of time as a conventional 2D scan. The production of the 3D model takes between 15–60 minutes depending on the level of detail required. Distances are measurable to within ±0.4mm meaning fracture gaps of sub-millimeter width can be resolved. The system has already been evaluated on healthy volunteers and a clinical study currently underway.

Granular Cell Tumours are rare mesenchymal soft tissue tumours that arise throughout the body and are believed to be of neural origin. They often present as an asymptomatic slow-growing benign solitary lesion but may be multifocal. One to two percent of cases are malignant and can metastasise.

Described series in the literature are sparse. We examined our database and identified eleven cases in ten patients treated surgically and followed-up for a period of over six years (May 2002 to January 2009) in our regional bone and soft tissue tumour centre.

Five tumours were located in the lower limb, four in the upper limb and two in the axial skeleton. Mean patient age was 31.2 years (range 8 to 55 years). Excision was complete in one case, marginal in five cases and intra-lesional in five cases. No specimens showed evidence of malignancy. No patients required postoperative adjuvant treatment. Mean follow-up was 19.3 months (range 1 to 37 months), with no cases of local recurrence. One case was multi-focal.

Histopathological examination revealed the classical features of granular cell tumour in all cases. Typically, tumour cells were diffusely and strongly positive for S100 protein by immunohistochemistry, whereas the other markers tested were negative.

We believe this case series to be the largest of its type in patients presenting to an orthopaedic soft tissue tumour unit. We present our findings and correlate it with findings of other series in the literature.

Purpose

Developmental exposure to estrogens has been shown to affect a number of organ systems, including long and short bones. Epigenetic effects of DES exposure have been shown to affect the third generation of progeny. Furthermore, recent studies have shown that environmental exposure to estrogen-like compounds is much higher than originally anticipated. This study aims to discover the effect of in utero exposure to a well-known estrogen agonist, diethylstilbestrol (DES), on lumbar bone, intervertebral disc (IVD), and articular cartilage. Femoral bone was studied to determine the specificity of the effect.

Imaging can provide valuable information about the function of tissues and organs. The capacity for detecting and measuring imaging biomarkers of biological activities, allows for a better understanding of the pathophysiology of any process in the human body, including the musculoskeletal system. This is of particular importance in oncologic, metabolic and rheumatologic diseases, but not limited to these. In the domain of the musculoskeletal system, functional imaging also means to be able to address biomechanical evaluations. Weight-bearing imaging and dynamic studies have a prominent role. All imaging techniques (X-rays, CT, MR, ultrasound) are in demand, and offer different applications, specific equipment and novel methods for addressing this. Functional imaging is also essential to drive minimally invasive treatments – i.e. interventional radiology, and new treatment approaches move together with the advances on imaging guidance methods. On both the diagnostic and the interventional side, the increasing availability of dedicated equipment and the development of specific imaging methods and protocols greatly helps the transition from research to clinical practice

Aims. Tenosynovial giant cell tumour (TGCT) is a rare benign tumour of the musculoskeletal system. Surgical management is fraught with challenges due to high recurrence rates. The aim of this study was to describe surgical treatment and evaluate surgical outcomes of TGCT at an Australian tertiary referral centre for musculoskeletal tumours and to identify factors affecting recurrence rates. Methods. A prospective database of all patients with TGCT surgically managed by two orthopaedic oncology surgeons was reviewed. All cases irrespective of previous treatment were included and patients without follow-up were excluded. Pertinent tumour characteristics and surgical outcomes were collected for analysis. Results. There were 111 total cases included in the study; 71 (64%) were female, the mean age was 36 years (SD 13.6), and the knee (n = 64; 57.7%) was the most commonly affected joint. In all, 60 patients (54.1%) had diffuse-type (D-TGCT) disease, and 94 patients (84.7%) presented therapy-naïve as "primary cases" (PC). The overall recurrence rate was 46.8% for TGCT. There was a statistically significant difference in recurrence rates between D-TGCT and localized disease (75.0% vs 13.7%, relative risk (RR) 3.40, 95% confidence interval (CI) 2.17 to 5.34; p < 0.001), and for those who were referred in the ”revision cases” (RC) group compared to the PC group (82.4% vs 48.9%, RR 1.68, 95% CI 1.24 to 2.28; p = 0.011). Age, sex, tumour volume, and mean duration of symptoms were not associated with recurrence (p > 0.05). Conclusion. Recurrence rates remain high even at a tertiary referral hospital. Highest rates are seen in D-TGCT and “revision cases”. Due to the risks of recurrence, the complexity of surgery, and the need for adjuvant therapy, this paper further supports the management of TGCT in a tertiary referral multi-disciplinary orthopaedic oncology service. Cite this article: Bone Jt Open 2023;4(11):846–852

Our musculoskeletal system has a limited capacity for repair. This has led to increased interest in the development of tissue engineering and biofabrication strategies for the regeneration of musculoskeletal tissues such as bone, ligament, tendon, meniscus and articular cartilage. This talk will demonstrate how different musculoskeletal tissues, specifically cartilage, bone and osteochondral defects, can be repaired using emerging biofabrication and 3D bioprinting strategies. This will include examples from our lab where cells and/or growth factors are bioprinted into constructs that can be implanted directly into the body, to approaches where biomimetic tissues are first engineered in vitro before in vivo implantation. The efficacy of these different biofabrication strategies in different preclinical studies will be reviewed, and lessons from the relative successes and failures of these approaches to tissue regeneration will be discussed

Osteotomies in the musculoskeletal system are joint preserving procedures to correct the alignment of the patient. In the lower limb, most of the pre-operative planning is performed on full leg weightbearing radiographs. However, these images contain a 2-dimensional projection of a 3-dimensional deformity, lack a clear visualization of the joint surface and are prone to rotational errors during patient positioning. Weightbearing CT imaging has demonstrated to overcome these shortcomings during the first applications of this device at level of the foot and ankle. Recent advances allow to scan the entire lower limb and novel applications at the level of the knee and hip are on the rise. Here, we will demonstrated the current techniques and 3-dimensional measurements used in supra- and inframalleolar osteotomies around the ankle. Several of these techniques will be transposed to other parts in the lower limb to spark future studies in this field

Geometric deep learning is a relatively new field that combines the principles of deep learning with techniques from geometry and topology to analyze data with complex structures, such as graphs and manifolds. In orthopedic research, geometric deep learning has been applied to a variety of tasks, including the analysis of imaging data to detect and classify abnormalities, the prediction of patient outcomes following surgical interventions, and the identification of risk factors for degenerative joint disease. This review aims to summarize the current state of the field and highlight the key findings and applications of geometric deep learning in orthopedic research. The review also discusses the potential benefits and limitations of these approaches and identifies areas for future research. Overall, the use of geometric deep learning in orthopedic research has the potential to greatly advance our understanding of the musculoskeletal system and improve patient care

Non-linear methods in statistical shape analysis have become increasingly important in orthopedic research as they allow for more accurate and robust analysis of complex shape data such as articulated joints, bony defects and cartilage loss. These methods involve the use of non-linear transformations to describe shapes, rather than the traditional linear approaches, and have been shown to improve the precision and sensitivity of shape analysis in a variety of applications. In orthopedic research, non-linear methods have been used to study a range of topics, including the analysis of bone shape and structure in relation to osteoarthritis, the assessment of joint deformities and their impact on joint function, and the prediction of patient outcomes following surgical interventions. Overall, the use of non-linear methods in statistical shape analysis has the potential to advance our understanding of the relationship between shape and function in the musculoskeletal system and improve the diagnosis and treatment of orthopedic conditions

Cerebral palsy (CP) is a neural condition that impacts and impairs the musculoskeletal system. Skeletal muscles, particularly in the lower limb, have previously been shown to be significantly reduced in volume in CP compared to typical controls. Muscle volume is a gross measure, however, and does not capture shape characteristics which—if quantified—could offer a robust and novel assessment of how this condition impacts skeletal muscle form and function in CP. In this study, we used mathematical shape modelling to quantify not just size, but also the shape, of soleus muscles in CP and typically developing (TD) cohorts to explore this question. Shape modelling is a mathematical technique used previously for bones, organs, and tumours. We obtained segmented muscle data from prior MRI studies in CP. We generated shape models of CP and TD cohorts and used our shape models to assess similarities and differences between the cohorts, and we statistically analysed shape differences. The shape models revealed similar principal components (PCs), i.e. the defining mathematical features of each shape, yet showed greater shape variability within the CP cohort. The model revealed a distinct feature (a superior –> inferior shift of the broad central region), indicating the model could identify muscular features that were not apparent with direct observation. Two PCs dominated the differences between CP and TD cohorts: size and aspect ratio (thinness) of the muscle. The distinct appearance characteristic in the CP model correspond to specific muscle impairments in CP to be discussed further. Overall, children with CP had smaller muscles that also tended to be long, thin, and narrow. Shape modelling captures shape features quantitatively, which indicate the ways that muscles are being impacted in CP. In the future, we hope to tailor this technique toward informing diagnosis and treatments in CP

In the context of regenerative medicine for the treatment of musculoskeletal pathologies mesenchymal stromal cells (MSCs) have shown good results thanks to secretion of therapeutic factors, both free and conveyed within the extracellular vesicles (EV), which in their totality constitute the “secretome”. The portfolio and biological activity of these molecules can be modulated by both in vitro and in vivo conditions, thus making the analysis of these activities very complex. A deep knowledge of the targets regulated by the secretome has become a matter of fundamental importance and a homogeneous and complete molecular characterization is still lacking in the field of applications for the musculoskeletal system. Therefore, the aim of this work was to characterize the secretome obtained from adipose-derived MSCs (ASCs), and its modulation after pre-conditioning of the ASCs. Pre-conditioning was done by culturing cells in the presence of i) high levels of IFNγ, as proposed for the production of clinical grade secretome with enhanced regenerative potential, ii) low levels of inflammatory stimuli, mimicking conditions found in the osteoarthritis (OA) synovial fluid. Furthermore, EVs ability to migrate within cartilage, chondrocyte and synoviocytes obtained from OA patients was evaluated. The data showed that more than 50 cytokines / chemokines and more than 200 EV-microRNAs are detectable at various intensity levels in ASCs secretomes. The majority of the most abundantly present molecules are involved in the remodelling of the extracellular matrix and in the homeostasis and chemotaxis of inflammatory cells including macrophages, which in OA are often characterized by an M1 inflammatory polarization, promoting their transition to an M2 anti-inflammatory phenotype. Inflammatory priming with IFNγ and synovial fluid-like conditions were able to further increase the ability of the secretome to interact with inflammatory cells and modulate their migration. Finally, the penetration of the EVs in the cartilage explants resulted a rapid process, which begins a few minutes after administration of the EVs that are able to reach a depth of 30-40 μm in 5 hours. The same capacity for interaction was also verified in chondrocytes and synoviocytes isolated from the cartilage and synovial membrane of OA patients. Thanks to the soluble factors and EV-microRNAs, the ASCs secretome has shown a strong propensity to modulate the inflammatory and degenerative processes that characterize OA. The inflammatory pre-conditioning through high concentrations of inflammatory molecules or in conditions similar to the synovial fluid of OA patients was able to increase this capacity by increasing their chemotactic power. The microscopy data also support the hypothesis of the ability of MSC-EVs to influence the chondrocytes residing in the ECM of the cartilage and the synovial cells of the synovial membrane through active interaction and the release of their therapeutic content

Spinal deformations are posture dependent. Official data from the Netherlands show that youth are encountering increasing problems with the musculoskeletal system (>40% back pain, and sport injury proneness). Prolonged sloth and slumped sitting postures are causative factors. Dutch youth are “champion sitting” in Europe. The effects of sitting on the development of posture and function of locomotion (stiffness) during growth have only been reported clearly in classic textbooks (in German) of practical anatomy and orthopaedics. Research with relevant clinical examinations is being done to understand epidemiological data on the increasing posture-dependent problems. A cohort of adolescents (15–18 years) in secondary school was assessed for sagittal postural deviations while bending. 248 children completed a questionnaire, and tests were done on neuromuscular tightness. The femorotibial angle was used to measure hamstring tightness. Measurement of the dorsiflexion of the foot was used to assess the tightness of calf muscles and Achilles tendons. All adolescents were photographed laterally while performing the finger–floor test (used to test flexibility), assessed as a knockout test: “Can you reach the floor or not?” The spinal profiles while bending were classified as abnormal arcuate or angular kyphosis. Hamstring tightness was present in 62.1% of the cohort in both legs, and in 18.2% unilaterally. Achilles tendon tightness was present bilaterally in 59.3%, and unilaterally in 19.4%. Activities with presence of stiffness (finger–floor distance), in descending order, were football, running, no sports, field hockey, tennis, dance, and gymnastics. 93.5% of the soccer players had tight hamstrings in both legs compared with none of those performing gymnastics. The correlation of the finger–floor test with tight hamstrings was 73.2%. For sagittal bending deformities, the correlation between form and function deficits cannot be made yet. 80 of 248 spines were rated by the examiners as having deformed flexion. Since Andry (1741) and at the zenith of continental orthopaedics and anatomy around 1900, the prolonged flexed positions of a young spine were indicated as being the main cause of deformity by overload and shear loads on immature discs and cartilage, preventing normal development of the discs. Nachemson proved that the intradiscal pressure in sitting adults was extremely high, so it follows that children must also be at risk. Evidence suggests that youth, generally because of their sedentary and “screenful lifestyle”, will encounter serious problems in growth, manifesting as incongruent neuro-osseous growth (Roth), serious neuromuscular tightness (being prone to injury), and spinal deformations, leading to pain

Introduction. Hip dysplasia is the most common congenital deformity of the musculoskeletal system. This is a pathology that brings the hip joint from subluxation to dislocation. Frequency of hip dysplasia − 16 children per 1000 newborns. Materials and Methods. Diagnostic methods of research are X-ray inspection which is necessarily carried out at internal rotation (rotation) of an extremity as lateral rotation of a hip on the radiograph always increases an angle of a valgus deviation of a neck. Surgical treatment is performed in the subclavian area of the femur. An external fixation device is applied and a corrective corticotomy is performed, and valgus deformity and anteversion are eliminated. The duration of treatment is 2.5–3 months. Results. Frequency of hip dysplasia − 16 children per 1000 newborns. We perform about 30 operations a year, including 60% girls and 40% boys. In addition, valgus deformity can be traced -. - in cerebral palsy. - after polio. - at progressing muscular dystrophies. - tumor in the area of the epiphyseal cartilage. At insufficient stability in a hip joint at insufficiently expressed roof of an acetabulum of rotational deformation of a neck of a hip, for prevention of a coxarthrosis and normalization of a ratio of articular ends operation detorsion-varying subvertebral corticotomy of a femur is shown. Conclusions. The operation is minimally invasive, with accesses of 5–6 mm, anatomical and topographical features are taken into account, which will eliminate damage to tissues, nerve trunks and the circulatory system

The human musculoskeletal system is a biological composite of hard and soft material phases organized into a complex 3D structure. The replication of mechanical properties in 3-dimensional space, so called ‘4D’ techniques, therefore promises next-generation of prosthetics and engineering structures for the musculoskeletal system. Approaches using in situ indentation of tissue correlated with micro computed tomography (μCT) are used here to provide a 4D data set that is representative of the native tissue at high fidelity. Multi-material 3D printing is exploited to realize the collected 4D data set by using materials with a wide range of mechanical properties and printing structures representative of native tissue. We demonstrate this correlative approach to reproduce bone structures and highlight a workflow approach of indentation, μCT and 3D printing to potentially mimic any structure found in the musculoskeletal system. Structures in the human musculoskeletal system, such as bone [1] and tendon-bone connective tissue [2], can be considered as complex composites of hard and soft materials. Development of prosthetics capable of replacing body parts lost to trauma, disease or congenital conditions requires the accurate replication of the required body part. 3D printing promises considerable advantages over other manufacturing methods in mimicking native tissue, including the ability to produce complex structures [3]. However, accurate representation of whole body parts down to tissue microstructures requires correlative approaches where mechanical properties in 3-dimensional space are known. The objective of this study is to apply in situ indentation, correlate to 3D imaging of bone using μCT and finally 3D print mimicked structures. Samples of bovine compact bone were imaged at high resolution using μCT (Xradia Versa 510, Zeiss, USA). A custom build in situ micro indentation setup within the μCT was used to map the mechanical properties of the bone at multiple positions. Correlation between sample x-ray attenuation and corresponding elastic modulus found from indentation was established. Data was converted to a 4D data set of elastic modulus values in 3D space, segmented and exported to the 3D printer. An inkjet 3D printer (Projet 5500X, 3D Systems, USA) was used to print materials with a range of mechanical properties that approach those found in the native bone material. Macroscopic testing on both bone samples and 3D printed samples were carried out using standard compression (Instron, UK). Preliminary results indicated similarity between 3D printed structures and native bone tissue. Macroscopic testing of bone samples and 3D printed equivalents showed additional similarities in stress-strain behaviour. Our preliminary work presented here indicates that the workflow of 3D imaging correlated to point mechanical measurements using indentation is suitable to give a 4D dataset that is representative of the native bone tissue. 3D printing is able to produce structures that start to mimick bone but are critically dependent on the data segmentation, particularly averaging imaging data to a resolution that is appropriate for the 3D printer

Objectives. The aim of this study was to review the impact of smoking tobacco on the musculoskeletal system, and on bone fractures in particular. Methods. English-language publications of human and animal studies categorizing subjects into smokers and nonsmokers were sourced from MEDLINE, The Cochrane Library, and SCOPUS. This review specifically focused on the risk, surgical treatment, and prevention of fracture complications in smokers. Results. Smokers have an increased risk of fracture and experience more complications with delayed bone healing, even if they have already stopped smoking, because some adverse effects persist for a prolonged period. Some risks can be reduced during and after surgery by local and general prevention, and smoking cessation is an important factor in lessening this risk. However, if a patient wants to stop smoking at the time of a fracture, the cessation strategies in reducing tobacco use are not easy to implement. The patient should also be warned that using e-cigarettes or other tobaccos does not appear to reduce adverse effects on health. Conclusion. The evidence reviewed in this study shows that smoking has a negative effect in terms of the risk and treatment of fractures. Cite this article: J. Hernigou, F. Schuind. Tobacco and bone fractures: A review of the facts and issues that every orthopaedic surgeon should know. Bone Joint Res 2019;8:255–265. DOI: 10.1302/2046-3758.86.BJR-2018-0344.R1

Calcium is an important element for a wide range of physiological functions including muscle contraction, neuronal activity, exocytosis, blood coagulation and cell communication. In the musculoskeletal system calcium is crucial for the structural integrity of bones, teeth, intervertebral disc and articular cartilage. At the cellular level calcium acts as a second messenger. Calcium signalling uses intracellular calcium ions to drive intracellular communication and signal transduction processes. When calcium enters the cell it exerts allosteric regulatory effects on many enzymes and proteins. Examining the role of calcium in chondrocyte biology is important for understanding the role for this divalent ion in the metabolic modulation of chondrocyte function in health and disease. This includes the study of calcium transport systems such as channels, transporters and pumps involved in calcium homeostasis in chondrocytes and how existing pharmacological drugs act on these transport systems. L-type calcium channel blockers are drugs used as cardiac antiarrhythmics or antihypertensives, depending on whether the drugs have higher affinity for the heart (the phenylalkylamines, like verapamil), or for the blood vessels (the dihydropyridines, like nifedipine). L-type calcium channels are present in many musculoskeletal tissues including skeletal muscle, smooth muscle, bone and cartilage. L-type calcium channel inhibitors like nifedipine used for the treatment of some forms of hypertension modulate calcium-mediated events in chondrocytes under dynamic loading, thus affecting metabolism, osmotic responses and extracellular matrix turnover in cartilage. The aim of our work is to understand the impact of L-type calcium channel inhibitors used for the treatment of hypertension on chondrocytes and on the chondrogenic differentiation of bone marrow derived mesenchymal stem cells (MSCs). This knowledge will enhance our understanding of the development of osteoarthritis (OA) and may lead to new opportunities for chondroprotection and regenerative medicine for OA. We have used electrophysiology to demonstrate L-type calcium currents in chondrocytes immediately after pharmacological activation with the calcium channel opener Bay-K8644. We have also used immunohistochemistry to demonstrate expression of the a1C subunit Ca. v. 1.2 (CACNA1C) in human chondrocytes and MSCs. Inhibitors of L-type calcium channels such as nifedipine downregulate mitochondrial respiration and ATP production in MSCs but not in chondrocytes. Nifedipine inhibits proliferation of chondrocytes and enhances glycolytic capacity in chondrocytes, promoting glycolytic reserve in both MSCs and chondrocytes. Nifedipine can also stimulate chondrogenic differentiation in MSCs (with or without growth factors). Metabolic responses to nifedipine differs in mesenchymal stem cells and chondrocytes highlighting important metabolic differences between these cells. In summary, antihypertensive drugs such as nifedipine can affect the biological function of chondrocytes and MSCs and may modulate the course of OA progression and impact on cartilage repair

Objective. Modic changes (MC), a form of intervertebral disc degeneration visible as subchondral and vertebral bone marrow changes on spine magnetic resonance (MR), are known to be associated with low back pain. This study aimed to identify genes contributing to the development of MC using genome-wide association study. Methods. Presence of MC was evaluated in lumbar MR images in the Northern Finland Birth Cohort 1966 (NFBC1966, N=1182) and TwinsUK (N=647). Genome-wide association analyses were carried out in the cohorts separately using a linear regression model fitted to test for additive effects of SNPs and adjusting for age, sex, BMI, and either family relatedness via a kinship matrix (TwinsUK) or population stratification using principal components (NFBC1966). Meta-analysis of the two studies was carried out using the inverse-variance weighting approach. Results. A locus associated with MC reaching genome-wide significance (p<5e-8) was found on chromosome 9 with the lead SNP rs1934268 in intron 6 of the PTPRD gene. The SNP is located in the region of binding for a number of transcription factors which are involved in the development of the musculoskeletal system and spine cord. Conclusions. The first GWAS of MC has identified a likely functional intronic locus in PTPRD on chromosome 9 implicating musculoskeletal development. This work sheds light on the genesis of MC and paves the way for further studies on the shared genetic factors underlying the various features of spine degeneration. No conflicts of interest. Sources of Funding: The study was supported by EU FP7 project PainOMICs (grant agreement #602736), University of Oulu (grant #24000692), Oulu University Hospital (grant #24301140), and the European Regional Development Fund (grant # 539/2010 A31592). MBF, MK, and SS contributed equally to this study