Novel Insights into the Links between N6-Methyladenosine and Regulated Cell Death in Musculoskeletal Diseases.

Musculoskeletal diseases (MSDs), including osteoarthritis (OA), osteosarcoma (OS), multiple myeloma (MM), intervertebral disc degeneration (IDD), osteoporosis (OP), and rheumatoid arthritis (RA), present noteworthy obstacles associated with pain, disability, and impaired quality of life on a global scale. In recent years, it has become increasingly apparent that N6-methyladenosine (m6A) is a key regulator in the expression of genes in a multitude of biological processes. m6A is composed of 0.1-0.4% adenylate residues, especially at the beginning of 3'-UTR near the translation stop codon. The m6A regulator can be classified into three types, namely the "writer", "reader", and "eraser". Studies have shown that the epigenetic modulation of m6A influences mRNA processing, nuclear export, translation, and splicing. Regulated cell death (RCD) is the autonomous and orderly death of cells under genetic control to maintain the stability of the internal environment. Moreover, distorted RCDs are widely used to influence the course of various diseases and receiving increasing attention from researchers. In the past few years, increasing evidence has indicated that m6A can regulate gene expression and thus influence different RCD processes, which has a central role in the etiology and evolution of MSDs. The RCDs currently confirmed to be associated with m6A are autophagy-dependent cell death, apoptosis, necroptosis, pyroptosis, ferroptosis, immunogenic cell death, NETotic cell death and oxeiptosis. The m6A-RCD axis can regulate the inflammatory response in chondrocytes and the invasive and migratory of MM cells to bone remodeling capacity, thereby influencing the development of MSDs. This review gives a complete overview of the regulatory functions on the m6A-RCD axis across muscle, bone, and cartilage. In addition, we also discuss recent advances in the control of RCD by m6A-targeted factors and explore the clinical application prospects of therapies targeting the m6A-RCD in MSD prevention and treatment. These may provide new ideas and directions for understanding the pathophysiological mechanism of MSDs and the clinical prevention and treatment of these diseases.

Keeping it real: Merging traditional and contemporary practices in musculoskeletal pathology: A special issue of neoplastic and non-neoplastic bone and soft tissue pathology.

There is no shortage of comprehensive review articles on bone and soft tissue pathology, almost always representing a regurgitation of the literature with little to no guidance on personal "best practices," recommended applications of ancillary testing, and alternative points of view. This special issue of Human Pathology uniquely unites evidence-based medicine, where appropriate, with the collective personal experiences of a wide range of accomplished pathologists from varying institutions and backgrounds, addressing problematic areas, updated and sometimes imperfect classification systems, and their personal preferences for cost-effectively incorporating ancillary testing. For the preponderance of general pathologists (and specialists), whether academic or non-academic, non-neoplastic musculoskeletal diseases represent a far higher percentage of their practice than bone and soft tissue neoplasia. One of the most common frozen sections performed at many hospitals throughout the USA is revision arthroplasty, relying on the pathologist to help determine the presence (or absence) of periprosthetic joint infection, largely based on the hematoxylin & eosin (H&E) slide. Not every institution has access to the latest molecular techniques; fortunately, many of the current immunohistochemical antibodies serve as reliable surrogate markers of genetic mutations, allowing for cheaper but accurate diagnoses, when deemed necessary. Furthermore, molecular testing is often not necessary to establish a specific diagnosis, even among neoplasms with known underlying genetic abnormalities. It must be remembered that most bone and soft tissue tumors were recognized and classified correctly, before we uncovered and understood, among a subset, their underlying and unique molecular aberrations. Perhaps not surprisingly, in some cases, more than one molecular pathway may lead to the same histologic tumor subtype. Less commonly, an identical genetic driver/fusion may result in immunophenotypically and biologically distinct neoplasms, sometimes with entirely different clinical behaviors. "Dedifferentiation," a concept recognized among a variety of bone and soft tissue neoplasms, including but not limited to chondrosarcoma, parosteal osteosarcoma, and liposarcoma, needs to be objectively reassessed, particularly for liposarcoma. The following reviews attempt to address the above concepts, re-emphasizing the important role the practicing pathologist continues to (and must) play in the differential diagnoses of neoplastic and non-neoplastic musculoskeletal diseases.

Investigation of perfusion impairment in degenerative cervical myelopathy beyond the site of cord compression.

The aim of this study was to determine tissue-specific blood perfusion impairment of the cervical cord above the compression site in patients with degenerative cervical myelopathy (DCM) using intravoxel incoherent motion (IVIM) imaging. A quantitative MRI protocol, including structural and IVIM imaging, was conducted in healthy controls and patients. In patients, T2-weighted scans were acquired to quantify intramedullary signal changes, the maximal canal compromise, and the maximal cord compression. T2*-weighted MRI and IVIM were applied in all participants in the cervical cord (covering C1-C3 levels) to determine white matter (WM) and grey matter (GM) cross-sectional areas (as a marker of atrophy), and tissue-specific perfusion indices, respectively. IVIM imaging resulted in microvascular volume fraction ([Formula: see text]), blood velocity ([Formula: see text]), and blood flow ([Formula: see text]) indices. DCM patients additionally underwent a standard neurological clinical assessment. Regression analysis assessed associations between perfusion parameters, clinical outcome measures, and remote spinal cord atrophy. Twenty-nine DCM patients and 30 healthy controls were enrolled in the study. At the level of stenosis, 11 patients showed focal radiological evidence of cervical myelopathy. Above the stenosis level, cord atrophy was observed in the WM (- 9.3%; p = 0.005) and GM (- 6.3%; p = 0.008) in patients compared to healthy controls. Blood velocity (BV) and blood flow (BF) indices were decreased in the ventral horns of the GM (BV: - 20.1%, p = 0.0009; BF: - 28.2%, p = 0.0008), in the ventral funiculi (BV: - 18.2%, p = 0.01; BF: - 21.5%, p = 0.04) and lateral funiculi (BV: - 8.5%, p = 0.03; BF: - 16.5%, p = 0.03) of the WM, across C1-C3 levels. A decrease in microvascular volume fraction was associated with GM atrophy (R = 0.46, p = 0.02). This study demonstrates tissue-specific cervical perfusion impairment rostral to the compression site in DCM patients. IVIM indices are sensitive to remote perfusion changes in the cervical cord in DCM and may serve as neuroimaging biomarkers of hemodynamic impairment in future studies. The association between perfusion impairment and cervical cord atrophy indicates that changes in hemodynamics caused by compression may contribute to the neurodegenerative processes in DCM.

Is the type and/or co-existence of degenerative spinal pathology associated with the occurrence of degenerative cervical myelopathy? A single centre retrospective analysis of individuals with MRI defined cervical cord compression.

BACKGROUND: Degenerative cervical myelopathy (DCM) arises from spinal degenerative changes injuring the cervical spinal cord. Most cord compression is incidental, referred to as asymptomatic spinal cord compression (ASCC). How and why ASCC differs from DCM is poorly understood. In this paper, we study a local cohort to identify specific types and groups of degenerative pathology more likely associated with DCM than ASCC. METHODS: This study was a retrospective cohort analysis (IRB Approval ID: PRN10455). The frequency of degenerative findings between those with ASCC and DCM patients were compared using network analysis, hierarchical clustering, and comparison to existing literature to identify potential subgroups in a local cohort (N = 155) with MRI-defined cervical spinal cord compression. Quantitative measures of spinal cord compression (MSCC and MCC) were used to confirm their relevance. RESULTS: ELF (8.7 %, 95 % CI 3.8-13.6 % vs 35.7 %, 95 % CI 27.4-44.0 %) Congenital Stenosis (3.9 %, 95 % CI 0.6-7.3 % vs 25.0 %, 95 % CI 17.5-32.5 %), and OPLL (0.0 %, 95 % CI 0.0-0.0 % vs 3.6 %, 95 % CI 0.3-6.8 %) were more likely in patients with DCM. Comparative network analysis indicated loss of lordosis was associated with ASCC, whilst ELF with DCM. Hierarchical Cluster Analysis indicated four sub-groups: multi-level disc disease with ELF, single-level disc disease without loss of lordosis and OPLL with DCM, and single-level disc disease with loss of lordosis with ASCC. Quantitative measures of cord compression were higher in groups associated with DCM, but similar in patients with single-level disc disease and loss of lordosis. CONCLUSIONS: This study identified four subgroups based on degenerative pathology requiring further investigation.

Potential therapeutic targets of macrophages in inhibiting immune damage and fibrotic processes in musculoskeletal diseases.

Macrophages are a heterogeneous cell type with high plasticity, exhibiting unique activation characteristics that modulate the progression and resolution of diseases, serving as a key mediator in maintaining tissue homeostasis. Macrophages display a variety of activation states in response to stimuli in the local environment, with their subpopulations and biological functions being dependent on the local microenvironment. Resident tissue macrophages exhibit distinct transcriptional profiles and functions, all of which are essential for maintaining internal homeostasis. Dysfunctional macrophage subpopulations, or an imbalance in the M1/M2 subpopulation ratio, contribute to the pathogenesis of diseases. In skeletal muscle disorders, immune and inflammatory damage, as well as fibrosis induced by macrophages, are prominent pathological features. Therefore, targeting macrophages is of great significance for maintaining tissue homeostasis and treating skeletal muscle disorders. In this review, we discuss the receptor-ligand interactions regulating macrophages and identify potential targets for inhibiting collateral damage and fibrosis in skeletal muscle disorders. Furthermore, we explore strategies for modulating macrophages to maintain tissue homeostasis.

Fast, non-eccentrically loaded exercise worsens tendinopathic healing responses in a murine model.

OBJECTIVE: To advance the understanding of how alterations in exercise speed and grade (flat vs 17° incline or decline) affect the quality of tendon healing, and to determine if a biomarker relationship exists between serum levels of a ColX breakdown product (CXM) and animals exposed to treadmill running protocols. ANIMALS: 35 male mice (C57BL/6J), 8 weeks of age. PROCEDURES: Mice were preconditioned on a treadmill for 14 days. Tendinopathy was then induced by 2 intra-tendinous TGFß1 injections followed by randomization into 7 exercise groups. Exercise capacity and objective gait analysis were measured weekly. Mice were euthanized and histopathologic analysis and evaluation of serum CXM levels were performed. Statistics were conducted using a 2-way ANOVA (exercise capacity), Mixed Effects Model (gait analysis, effect of preconditioning), and 1-way ANOVA (gait analysis, the effect of injury, and rehabilitation normalized to baseline; CXM serum analysis), all with Tukey post hoc tests and significance set to P < .05. RESULTS: Exercise at a fast-flat speed demonstrated inferior tendinopathic healing at the cellular level and impaired stance braking abilities, which were compensated for by increased propulsion. Mice exposed to exercise (at any speed or grade) demonstrated higher systemic levels of CXM than those that were cage rested. However, no ColX immunostaining was observed in the Achilles tendon or calcaneal insertion. CLINICAL RELEVANCE: Exercise at a fast speed and in absence of eccentric loading components (incline or decline) demonstrated inferior tendinopathic healing at the cellular level and impaired braking abilities that were compensated for by increased propulsion.

Percutaneous biopsy of musculoskeletal tumors and the potential for needle tract seeding: technical considerations, current controversies, and outcomes.

Multidisciplinary communication and planning between the musculoskeletal radiologist and orthopedic oncologist are essential for proper biopsy planning when a primary musculoskeletal malignancy is suspected. Image-guided percutaneous biopsy allows for real-time visualization of the biopsy needle and surrounding structures, combining high diagnostic accuracy with safety and cost-effectiveness. However, determining a surgically optimal biopsy trajectory for a mass can be technically challenging due to critical surrounding anatomy or challenging needle approach angles. Inappropriately placed biopsies can have serious repercussions on patient function and oncological survival. The potential for needle tract seeding and local recurrence after biopsy of sarcoma has been central to the debate regarding the need for excision of the biopsy tract. This multidisciplinary review highlights current controversies in the field, including the issue of core needle biopsy tracts and their excision, technical considerations and advances in image-guidance in the setting of challenging biopsies, advances in histopathological diagnostics with implications for targeted therapy in sarcoma, as well as surgical and oncological outcomes after needle tract biopsy.

Imaging features and biopsy yield of soft tissue metastatic lesions: 10-year single tertiary center experience.

OBJECTIVE: To evaluate imaging features of soft tissue metastases, technical factors associated with diagnostic yield of image-guided biopsy, and clinical impact of biopsy results on patient outcomes. MATERIALS AND METHODS: A total of 1605 image-guided soft tissue biopsies were retrospectively identified from December 2010 to December 2020. Included lesions were histologically proven musculoskeletal soft tissue metastases. Lesions were excluded if intraabdominal, intrathoracic, retroperitoneal, associated with osseous lesions or surgical scar implants or arising from skin or lymph nodes. Image guidance modality, needle size, number of cores, and lesion location, size, and depth from skin were recorded. Patient demographics, malignancy history, biopsy-driven changes in management, and survival rate after biopsy were collected. RESULTS: Forty-six patients met the inclusion criteria with a biopsy diagnostic yield of 44/46 (95.7%). Metastases were most commonly located truncal (82.6%, p < 0.001) and intramuscular (78.3%, p < 0.001). A total of 37/46 (80.4%) biopsies were US-guided. And 9/46 (19.6%) were CT-guided. There was no significant difference in the number of cores or mean needle gauge between diagnostic and nondiagnostic biopsies. At time of review, 23 (50%) patients were deceased, with a mean survival of 13.5 months after biopsy. The majority (71.7%) of patients had a known primary malignancy at time of biopsy, most commonly lung (24.2%) and breast (24.2%). Overall survival showed no association with anatomic location (p > 0.83) or tissue type (p > 0.34). The most common biopsy-driven outcome was initiation of chemotherapy, immunotherapy, and/or radiotherapy (52.2%). CONCLUSION: Image-guided biopsy for soft tissue metastases has high diagnostic yield and commonly influences clinical management. Metastases were most commonly intramuscular in the trunk and are associated with poor prognosis.

Quantitative MRI for Evaluation of Musculoskeletal Disease: Cartilage and Muscle Composition, Joint Inflammation, and Biomechanics in Osteoarthritis.

ABSTRACT: Magnetic resonance imaging (MRI) is a valuable tool for evaluating musculoskeletal disease as it offers a range of image contrasts that are sensitive to underlying tissue biochemical composition and microstructure. Although MRI has the ability to provide high-resolution, information-rich images suitable for musculoskeletal applications, most MRI utilization remains in qualitative evaluation. Quantitative MRI (qMRI) provides additional value beyond qualitative assessment via objective metrics that can support disease characterization, disease progression monitoring, or therapy response. In this review, musculoskeletal qMRI techniques are summarized with a focus on techniques developed for osteoarthritis evaluation. Cartilage compositional MRI methods are described with a detailed discussion on relaxometric mapping (T 2 , T 2 *, T 1ρ ) without contrast agents. Methods to assess inflammation are described, including perfusion imaging, volume and signal changes, contrast-enhanced T 1 mapping, and semiquantitative scoring systems. Quantitative characterization of structure and function by bone shape modeling and joint kinematics are described. Muscle evaluation by qMRI is discussed, including size (area, volume), relaxometric mapping (T 1 , T 2 , T 1ρ ), fat fraction quantification, diffusion imaging, and metabolic assessment by 31 P-MR and creatine chemical exchange saturation transfer. Other notable technologies to support qMRI in musculoskeletal evaluation are described, including magnetic resonance fingerprinting, ultrashort echo time imaging, ultrahigh-field MRI, and hybrid MRI-positron emission tomography. Challenges for adopting and using qMRI in musculoskeletal evaluation are discussed, including the need for metal artifact suppression and qMRI standardization.

Malos resultados y complicaciones en el uso de ondas de choque focales y ondas de presión radial en patología musculoesquelética / Poor results and complications in the use of focused shockwaves and radial pressure waves in musculoskeletal pathology

La aplicación de ondas de choque focales y de ondas de presión radial en patología musculoesquelética ha tenido un gran desarrollo y difusión en la última década. Si bien la mayoría de las publicaciones han resaltado su seguridad y eficacia, no están exentas de malos resultados y complicaciones. Esta revisión analiza las principales causas de los malos resultados, efectos adversos y complicaciones, haciendo énfasis en su prevención.(AU)

The application of focused shockwaves and radial pressure waves in musculoskeletal pathology has had a great development in the last decade. Although most of the publications have highlighted their safety and efficacy, poor results and complications can occur. This review analyzes the main causes of its poor results, adverse effects, and complications, emphasizing their prevention.(AU)

Musculoskeletal diseases among French military high-speed boat pilots.

In 2016, the French Navy acquired a new high-speed boat, called ECUME. It exposes crewmembers to significant Whole Body Vibrations. This work explores the musculoskeletal diseases among this population. We conducted a retrospective declarative epidemiologic study using anonymous questionnaires. Eighty-four sailors were included. Fifty-six (66.7%) report acute traumas during a nautical raid during the 12 months study period. Sixty (71.4%) report chronic pains, which they associate with their nautical activity. Among them, only 16 (26.7%) have consulted a doctor, but 32 (53.3%) report consuming medication, including 18 through selfmedication. More than half rely to alternatives medicine, especially osteopathy. The traumatic risk of ECUME riding is obvious. Many crewmembers minimize their symptoms, and consult rarely a physician. They give preference to selfmedication and alternative medicines.

MODOMICS: a database of RNA modification pathways. 2021 update.

The MODOMICS database has been, since 2006, a manually curated and centralized resource, storing and distributing comprehensive information about modified ribonucleosides. Originally, it only contained data on the chemical structures of modified ribonucleosides, their biosynthetic pathways, the location of modified residues in RNA sequences, and RNA-modifying enzymes. Over the years, prompted by the accumulation of new knowledge and new types of data, it has been updated with new information and functionalities. In this new release, we have created a catalog of RNA modifications linked to human diseases, e.g., due to mutations in genes encoding modification enzymes. MODOMICS has been linked extensively to RCSB Protein Data Bank, and sequences of experimentally determined RNA structures with modified residues have been added. This expansion was accompanied by including nucleotide 5'-monophosphate residues. We redesigned the web interface and upgraded the database backend. In addition, a search engine for chemically similar modified residues has been included that can be queried by SMILES codes or by drawing chemical molecules. Finally, previously available datasets of modified residues, biosynthetic pathways, and RNA-modifying enzymes have been updated. Overall, we provide users with a new, enhanced, and restyled tool for research on RNA modification. MODOMICS is available at https://iimcb.genesilico.pl/modomics/.

Insight into the pharmacological effects of andrographolide in musculoskeletal disorders.

Andrographis paniculata (A. paniculata) is a traditional herbal medicine that has been widely used in Asian countries for hundreds of years. Andrographolide (AG) is a diterpene lactone extracted from A. paniculata. Owing to the in-depth study of pharmacological mechanisms, the therapeutic potential of AG, including its anti-inflammatory, anti-tumor, and immunoregulatory attributes, has attracted the attention of many researchers. Studies testing the therapeutic effects of AG have demonstrated desirable results in the treatment of a variety of clinical diseases. With high safety and various biological functions, AG might be a promising candidate for the treatment of musculoskeletal disorders. Here, we review all available literatures to summarize the pharmacological effects of AG and facilitate further researches on musculoskeletal diseases.

Perspective of the GEMSTONE Consortium on Current and Future Approaches to Functional Validation for Skeletal Genetic Disease Using Cellular, Molecular and Animal-Modeling Techniques.

The availability of large human datasets for genome-wide association studies (GWAS) and the advancement of sequencing technologies have boosted the identification of genetic variants in complex and rare diseases in the skeletal field. Yet, interpreting results from human association studies remains a challenge. To bridge the gap between genetic association and causality, a systematic functional investigation is necessary. Multiple unknowns exist for putative causal genes, including cellular localization of the molecular function. Intermediate traits ("endophenotypes"), e.g. molecular quantitative trait loci (molQTLs), are needed to identify mechanisms of underlying associations. Furthermore, index variants often reside in non-coding regions of the genome, therefore challenging for interpretation. Knowledge of non-coding variance (e.g. ncRNAs), repetitive sequences, and regulatory interactions between enhancers and their target genes is central for understanding causal genes in skeletal conditions. Animal models with deep skeletal phenotyping and cell culture models have already facilitated fine mapping of some association signals, elucidated gene mechanisms, and revealed disease-relevant biology. However, to accelerate research towards bridging the current gap between association and causality in skeletal diseases, alternative in vivo platforms need to be used and developed in parallel with the current -omics and traditional in vivo resources. Therefore, we argue that as a field we need to establish resource-sharing standards to collectively address complex research questions. These standards will promote data integration from various -omics technologies and functional dissection of human complex traits. In this mission statement, we review the current available resources and as a group propose a consensus to facilitate resource sharing using existing and future resources. Such coordination efforts will maximize the acquisition of knowledge from different approaches and thus reduce redundancy and duplication of resources. These measures will help to understand the pathogenesis of osteoporosis and other skeletal diseases towards defining new and more efficient therapeutic targets.

ADSC-Based Cell Therapies for Musculoskeletal Disorders: A Review of Recent Clinical Trials.

Recently published clinical trials involving the use of adipose-derived stem cells (ADSCs) indicated that approximately one-third of the studies were conducted on musculoskeletal disorders (MSD). MSD refers to a wide range of degenerative conditions of joints, bones, and muscles, and these conditions are the most common causes of chronic disability worldwide, being a major burden to the society. Conventional treatment modalities for MSD are not sufficient to correct the underlying structural abnormalities. Hence, ADSC-based cell therapies are being tested as a form of alternative, yet more effective, therapies in the management of MSDs. Therefore, in this review, MSDs subjected to the ADSC-based therapy were further categorized as arthritis, craniomaxillofacial defects, tendon/ligament related disorders, and spine disorders, and their brief characterization as well as the corresponding conventional therapeutic approaches with possible mechanisms with which ADSCs produce regenerative effects in disease-specific microenvironments were discussed to provide an overview of under which circumstances and on what bases the ADSC-based cell therapy was implemented. Providing an overview of the current status of ADSC-based cell therapy on MSDs can help to develop better and optimized strategies of ADSC-based therapeutics for MSDs as well as help to find novel clinical applications of ADSCs in the near future.

LncRNAs as a new regulator of chronic musculoskeletal disorder.

OBJECTIVES: In recent years, long non-coding RNAs (lncRNAs) have been found to play a role in the occurrence, progression and prognosis of chronic musculoskeletal disorders. DESIGN AND METHODS: Literature exploring on PubMed was conducted using the combination of keywords 'LncRNA' and each of the following: 'osteoarthritis', 'rheumatoid arthritis', 'osteoporosis', 'osteogenesis', 'osteoclastogenesis', 'gout arthritis', 'Kashin-Beck disease', 'ankylosing spondylitis', 'cervical spondylotic myelopathy', 'intervertebral disc degeneration', 'human muscle disease' and 'muscle hypertrophy and atrophy'. For each disorder, we focused on the publications in the last five years (5/1/2016-2021/5/1, except for Kashin-Beck disease). Finally, we excluded publications that had been reported in reviews of various musculoskeletal disorders during the last three years. Here, we summarized the progress of research on the role of lncRNA in multiple pathological processes during musculoskeletal disorders. RESULTS: LncRNAs play a crucial role in regulating downstream gene expression and maintaining function and homeostasis of cells, especially in chondrocytes, synovial cells, osteoblasts, osteoclasts and skeletal muscle cells. CONCLUSIONS: Understanding the mechanisms of lncRNAs in musculoskeletal disorders may provide promising strategies for clinical practice.

The Role of Mesenchymal Stem Cells (MSCs) in Veterinary Medicine and Their Use in Musculoskeletal Disorders.

Regenerative medicine is a dynamically developing field of human and veterinary medicine. The animal model was most commonly used for mesenchymal stem cells (MSCs) treatment in experimental and preclinical studies with a satisfactory therapeutic effect. Year by year, the need for alternative treatments in veterinary medicine is increasing, and other applications for promising MSCs and their biological derivatives are constantly being sought. There is also an increase in demand for other methods of treating disease states, of which the classical treatment methods did not bring the desired results. Cell therapy can be a realistic option for treating human and animal diseases in the near future and therefore additional research is needed to optimize cell origins, numbers, or application methods in order to standardize the treatment process and assess its effects. The aim of the following work was to summarize available knowledge about stem cells in veterinary medicine and their possible application in the treatment of chosen musculoskeletal disorders in dogs and horses.

Interactions between Gene Variants within the COL1A1 and COL5A1 Genes and Musculoskeletal Injuries in Physically Active Caucasian.

The COL1A1 and COL5A1 variants have been associated with the risk of musculoskeletal injuries. Therefore, the main aim of the study was to investigate the association between three polymorphisms within two genes (rs1800012 in COL1A1, as well as rs12722 and rs13946 in COL5A1) and the reported, yet rarely described in the literature, injuries of the joint and muscle area in a physically active Caucasian population. Polish students (n = 114) were recruited and divided into the following two groups: students with (n = 53) and without (n = 61) injures. Genotyping was carried out using real-time PCR. The results obtained revealed a statistically significant association between rs1800012 COL1A1 and injury under an overdominant model. Specifically, when adjusted for age and sex, the GT heterozygotes had a 2.2 times higher chance of being injured compared with both homozygotes (TT and GG, 95% CI 0.59-5.07, p = 0.040). However, no significant interaction between the COL5A1 variants, either individually or in haplotype combination, and susceptibility to injury were found. In addition, the gene-gene interaction analysis did not reveal important relationships with the musculoskeletal injury status. It was demonstrated that rs1800012 COL1A1 may be positively associated with physical activity-related injuries in a Caucasian population. Harboring the specific GT genotype may be linked to a higher risk of being injured.

Does the Interaction between Local and Systemic Inflammation Provide a Link from Psychology and Lifestyle to Tissue Health in Musculoskeletal Conditions?

Musculoskeletal conditions are known to involve biological, psychological, social and, often, lifestyle elements. However, these domains are generally considered in isolation from each other. This siloed approach is unlikely to be adequate to understand the complexity of these conditions and likely explains a major component of the disappointing effects of treatment. This paper presents a hypothesis that aims to provide a foundation to understand the interaction and integration between these domains. We propose a hypothesis that provides a plausible link between psychology and lifestyle factors with tissue level effects (such as connective tissue dysregulation/accumulation) in musculoskeletal conditions that is founded on understanding the molecular basis for interaction between systemic and local inflammation. The hypothesis provides plausible and testable links between mind and body, for which empirical evidence can be found for many aspects. We present this hypothesis from the perspective of connective tissue biology and pathology (fibrosis), the role of inflammation locally (tissue level), and how this inflammation is shaped by systemic inflammation through bidirectional pathways, and various psychological and lifestyle factors via their influence on systemic inflammation. This hypothesis provides a foundation for new consideration of the development and refinement of personalized multidimensional treatments for individuals with musculoskeletal conditions.

Age-related alterations and senescence of mesenchymal stromal cells: Implications for regenerative treatments of bones and joints.

The most common clinical manifestations of age-related musculoskeletal degeneration are osteoarthritis and osteoporosis, and these represent an enormous burden on modern society. Mesenchymal stromal cells (MSCs) have pivotal roles in musculoskeletal tissue development. In adult organisms, MSCs retain their ability to regenerate tissues following bone fractures, articular cartilage injuries, and other traumatic injuries of connective tissue. However, their remarkable regenerative ability appears to be impaired through aging, and in particular in age-related diseases of bones and joints. Here, we review age-related alterations of MSCs in musculoskeletal tissues, and address the underlying mechanisms of aging and senescence of MSCs. Furthermore, we focus on the properties of MSCs in osteoarthritis and osteoporosis, and how their changes contribute to onset and progression of these disorders. Finally, we consider current treatments that exploit the enormous potential of MSCs for tissue regeneration, as well as for innovative cell-free extracellular-vesicle-based and anti-aging treatment approaches.