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.

Role of the Osteocyte in Musculoskeletal Disease.

PURPOSE OF THE REVIEW: The purpose of this review is to summarize the role of the osteocyte in muscle atrophy in cancer patients, sarcopenia, spinal cord injury, Duchenne's muscular dystrophy, and other conditions associated with muscle deterioration. RECENT FINDINGS: One type of bone cell, the osteocyte, appears to play a major role in muscle and bone crosstalk, whether physiological or pathological. Osteocytes are cells living within the bone-mineralized matrix. These cells are connected to each other by means of dendrites to create an intricately connected network. The osteocyte network has been shown to respond to different types of stimuli such as mechanical unloading, immobilization, aging, and cancer by producing osteocytes-derived factors. It is now becoming clear that some of these factors including sclerostin, RANKL, TGF-ß, and TNF-α have detrimental effects on skeletal muscle. Bone and muscle not only communicate mechanically but also biochemically. Osteocyte-derived factors appear to contribute to the pathogenesis of muscle disease and could be used as a cellular target for new therapeutic approaches.

Decreased SIRT1 Activity Is Involved in the Acute Injury Response of Chondrocytes to Ex Vivo Injurious Mechanical Overload.

A better understanding of molecular events following cartilage injury is required to develop treatments that prevent or delay the onset of trauma-induced osteoarthritis. In this study, alterations to SIRT1 activity in bovine articular cartilage explants were evaluated in the 24 h following a mechanical overload, and the effect of pharmacological SIRT1 activator SRT1720 on acute chondrocyte injury was assessed. SIRT1 enzymatic activity decreased as early as 5 min following the mechanical overload, and remained suppressed for at least 24 h. The chondrocyte injury response, including apoptosis, oxidative stress, secretion of inflammatory mediators, and alterations in cartilage matrix expression, was prevented with pharmacological activation of SIRT1 in a dose-dependent manner. Overall, the results implicate SIRT1 deactivation as a key molecular event in chondrocyte injury following a mechanical impact overload. As decreased SIRT1 signaling is associated with advanced age, these findings suggest that downregulated SIRT1 activity may be common to both age-related and injury-induced osteoarthritis.

The role of myeloid derived suppressor cells in musculoskeletal disorders.

The immune system is closely linked to bone homeostasis and plays a pivotal role in several pathological and inflammatory conditions. Through various pathways it modulates various bone cells and subsequently sustains the physiological bone metabolism. Myeloid-derived suppressor cells (MDSCs) are a group of heterogeneous immature myeloid-derived cells that can exert an immunosuppressive function through a direct cell-to-cell contact, secretion of anti-inflammatory cytokines or specific exosomes. These cells mediate the innate immune response to chronic stress on the skeletal system. In chronic inflammation, MDSCs act as an inner offset to rebalance overactivation of the immune system. Moreover, they have been found to be involved in processes responsible for bone remodeling in different musculoskeletal disorders, autoimmune diseases, infection, and cancer. These cells can not only cause bone erosion by differentiating into osteoclasts, but also alleviate the immune reaction, subsequently leading to long-lastingly impacted bone remodeling. In this review, we discuss the impact of MDSCs on the bone metabolism under several pathological conditions, the involved modulatory pathways as well as potential therapeutic targets in MDSCs to improve bone health.

Emerging role of mesenchymal stem/stromal cells (MSCs) and MSCs-derived exosomes in bone- and joint-associated musculoskeletal disorders: a new frontier.

Exosomes are membranous vesicles with a 30 to 150 nm diameter secreted by mesenchymal stem/stromal cells (MSCs) and other cells, such as immune cells and cancer cells. Exosomes convey proteins, bioactive lipids, and genetic components to recipient cells, such as microRNAs (miRNAs). Consequently, they have been implicated in regulating intercellular communication mediators under physiological and pathological circumstances. Exosomes therapy as a cell-free approach bypasses many concerns regarding the therapeutic application of stem/stromal cells, including undesirable proliferation, heterogeneity, and immunogenic effects. Indeed, exosomes have become a promising strategy to treat human diseases, particularly bone- and joint-associated musculoskeletal disorders, because of their characteristics, such as potentiated stability in circulation, biocompatibility, low immunogenicity, and toxicity. In this light, a diversity of studies have indicated that inhibiting inflammation, inducing angiogenesis, provoking osteoblast and chondrocyte proliferation and migration, and negative regulation of matrix-degrading enzymes result in bone and cartilage recovery upon administration of MSCs-derived exosomes. Notwithstanding, insufficient quantity of isolated exosomes, lack of reliable potency test, and exosomes heterogeneity hurdle their application in clinics. Herein, we will deliver an outline respecting the advantages of MSCs-derived exosomes-based therapy in common bone- and joint-associated musculoskeletal disorders. Moreover, we will have a glimpse the underlying mechanism behind the MSCs-elicited therapeutic merits in these conditions.

Characterization of Histone Modifications in Late-Stage Rotator Cuff Tendinopathy.

The development and progression of rotator cuff tendinopathy (RCT) is multifactorial and likely to manifest through a combination of extrinsic, intrinsic, and environmental factors, including genetics and epigenetics. However, the role of epigenetics in RCT, including the role of histone modification, is not well established. Using chromatin immunoprecipitation sequencing, differences in the trimethylation status of H3K4 and H3K27 histones in late-stage RCT compared to control were investigated in this study. For H3K4, 24 genomic loci were found to be significantly more trimethylated in RCT compared to control (p < 0.05), implicating genes such as DKK2, JAG2, and SMOC2 in RCT. For H3K27, 31 loci were shown to be more trimethylated (p < 0.05) in RCT compared to control, inferring a role for EPHA3, ROCK1, and DEFß115. Furthermore, 14 loci were significantly less trimethylated (p < 0.05) in control compared to RCT, implicating EFNA5, GDF6, and GDF7. Finally, the TGFß signaling, axon guidance, and regulation of focal adhesion assembly pathways were found to be enriched in RCT. These findings suggest that the development and progression of RCT is, at least in part, under epigenetic control, highlighting the influence of histone modifications in this disorder and paving the way to further understand the role of epigenome in RCT.

The Mechano-Ubiquitinome of Articular Cartilage: Differential Ubiquitination and Activation of a Group of ER-Associated DUBs and ER Stress Regulators.

Understanding how connective tissue cells respond to mechanical stimulation is important to human health and disease processes in musculoskeletal diseases. Injury to articular cartilage is a key risk factor in predisposition to tissue damage and degenerative osteoarthritis. Recently, we have discovered that mechanical injury to connective tissues including murine and porcine articular cartilage causes a significant increase in lysine-63 polyubiquitination. Here, we identified the ubiquitin signature that is unique to injured articular cartilage tissue upon mechanical injury (the "mechano-ubiquitinome"). A total of 463 ubiquitinated peptides were identified, with an enrichment of ubiquitinated peptides of proteins involved in protein processing in the endoplasmic reticulum (ER), also known as the ER-associated degradation response, including YOD1, BRCC3, ATXN3, and USP5 as well as the ER stress regulators, RAD23B, VCP/p97, and Ubiquilin 1. Enrichment of these proteins suggested an injury-induced ER stress response and, for instance, ER stress markers DDIT3/CHOP and BIP/GRP78 were upregulated following cartilage injury on the protein and gene expression levels. Similar ER stress induction was also observed in response to tail fin injury in zebrafish larvae, suggesting a generic response to tissue injury. Furthermore, a rapid increase in global DUB activity following injury and significant activity in human osteoarthritic cartilage was observed using DUB-specific activity probes. Combined, these results implicate the involvement of ubiquitination events and activation of a set of DUBs and ER stress regulators in cellular responses to cartilage tissue injury and in osteoarthritic cartilage tissues. This link through the ER-associated degradation pathway makes this protein set attractive for further investigation in in vivo models of tissue injury and for targeting in osteoarthritis and related musculoskeletal diseases.

Therapeutic Effects of Platelet-Derived Extracellular Vesicles in a Bioengineered Tendon Disease Model.

Tendon injuries represent over 30-50% of musculoskeletal disorders worldwide, yet the available therapies do not provide complete tendon repair/regeneration and full functionality restoring. Extracellular vesicles (EVs), membrane-enclosed nanoparticles, have emerged as the next breakthrough in tissue engineering and regenerative medicine to promote endogenous tissue regeneration. Here, we developed a 3D human in vitro model mimicking the signature of pathological tendon and used it to evaluate the influence that different platelet-derived EVs might have in tendon tissue repair mechanisms. For this, different EV populations isolated from platelets, small EVs (sEVs) and medium EVs (mEVs), were added to the culture media of human tendon-derived cells (hTDCs) cultured on isotropic nanofibrous scaffolds. The platelet-derived EVs increased the expression of tenogenic markers, promoted a healthy extracellular matrix (ECM) remodeling, and the synthesis of anti-inflammatory mediators. These findings suggest that platelet EVs provided relevant biochemical cues that potentiated a recovery of hTDCs phenotype from a diseased to a healthy state. Thus, this study opens new perspectives for the translation of platelet-derived EVs as therapeutics.

The multifaced role of HtrA1 in the development of joint and skeletal disorders.

HtrA1 (High temperature requirement A1) family proteins include four members, widely conserved from prokaryotes to eukaryotes, named HtrA1, HtrA2, HtrA3 and HtrA4. HtrA1 is a serine protease involved in a variety of biological functions regulating many signaling pathways degrading specific components and playing key roles in many human diseases such as neurodegenerative disorders, pregnancy complications and cancer. Due to its role in the breakdown of many ExtraCellular Matrix (ECM) components of articular cartilage such as fibronectin, decorin and aggrecan, HtrA1 encouraged many researches on studying its role in several skeletal diseases (SDs). These studies were further inspired by the fact that HtrA1 is able to regulate the signaling of one of the most important cytokines involved in SDs, the TGFß-1. This review aims to summarize the data currently available on the role of HtrA1 in skeletal diseases such as Osteoporosis, Rheumatoid Arthritis, Osteoarthritis and Intervertebral Disc Degeneration (IDD). The use of HtrA1 as a marker of frailty in geriatric medicine would represent a powerful tool for identifying older individuals at risk of developing skeletal disorders, evaluating an appropriate intervention to improve quality care in these people avoiding or improving age-related SDs in the elderly population.

Bioinformatics Analysis and Experimental Verification Identify Downregulation of COL27A1 in Poor Segmental Congenital Scoliosis.

BACKGROUND: Congenital scoliosis (CS) represents the congenital defect disease, and poor segmental congenital scoliosis (PSCS) represents one of its types. Delayed intervention can result in disability and paralysis. In this study, we would identify the core biomarkers for PSCS progression through bioinformatics analysis combined with experimental verification. METHODS: This work obtained the GSE11854 expression dataset associated with somite formation in the GEO database, which covers data of 13 samples. Thereafter, we utilized the edgeR of the R package to obtain DEGs in this dataset. Then, GO annotation, KEGG analyses, and DO annotation of DEGs were performed by "clusterProfiler" of the R package. This study performed LASSO regression for screening the optimal predicting factors for somite formation. Through RNA sequencing based on peripheral blood samples from healthy donors and PSCS cases, we obtained the RNA expression patterns and screen out DEGs using the R package DESeq2. The present work analyzed COL27A1 expression in PSCS patients by the RT-PCR assay. RESULTS: A total of 443 genes from the GSE11854 dataset were identified as DEGs, which were involved in BP associated with DNA replication, CC associated with chromosomal region, and MF associated with ATPase activity. These DEGs were primarily enriched in the TGF-ß signaling pathway and spinal deformity. Further, LASSO regression suggested that 9 DEGs acted as the signature markers for somite formation. We discovered altogether 162 DEGs in PSCS patients, which were involved in BP associated with cardiac myofibril assembly and MF associated with structural constituent of muscle. However, these 162 DEGs were not significantly correlated with any pathways. Finally, COL27A1 was identified as the only intersected gene between the best predictors for somite formation and PSCS-related DEGs, which was significantly downregulated in PSCS patients. CONCLUSION: This work sheds novel lights on DEGs related to the PSCS pathogenic mechanism, and COL27A1 is the possible therapeutic target for PSCS. Findings in this work may contribute to developing therapeutic strategies for PSCS.

Application of bone metabolic parameters in the diagnosis of growing pains.

OBJECTIVE: The present study aimed to assess the diagnostic significance of serum bone metabolic parameters in children with growing pains (GPs). METHODS: All patients diagnosed with GP and healthy controls matched with age and gender were recruited at the outpatient clinic of Children's Hospital at Zhejiang University School of Medicine from August 2016 to August 2021. In all subjects, serum levels of calcium (Ca), phosphorus (P), procollagen type-I N-terminal (PINP), parathormone (PTH), 25-hydroxyvitamin D (25-(OH)D), osteocalcin (OC), N-terminal cross-linked telopeptides of type-I collagen (CTX), and tartrate-resistant acid phosphatase type 5b (TRACP5b) were investigated. The univariate analysis, multivariate logistic regression analysis, and receiver operating characteristic (ROC) curve were used to identify the bone metabolic parameters factors for diagnosing GP. RESULTS: We enrolled 386 children with GP and 399 healthy controls in present study. The mean age of GP group was 5.319 years, and, primarily, the subjects were preschool-age children. The gender ratio (male-to-female) was 1.27 in GP group. After adjusting for age and gender, we identified that the serum levels of Ca (p < 0.001, OR: 25.039), P (p = 0.018, OR: 2.681), PINP (p < 0.001, OR: 1.002), and PTH (p = 0.036, OR: 0.988) were independent diagnostic factors associated with GP. Area under curve (AUC) of the ROC curves was in the order: PINP (0.612) > Ca (0.599) > P (0.583) > PTH (0.541). A combination of independent diagnostic factors and multivariable logistic regression analysis provided a refined logistic regression model to improve the diagnostic potential, of which the AUC had reached 0.655. CONCLUSIONS: Serum levels of Ca, P, PINP, and PTH could be independent diagnostic factors associated with GP. The logistic model was significantly superior to bone metabolic parameters for diagnosing GP.

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/.

The Potential Use of Mesenchymal Stem Cells and Their Derived Exosomes for Orthopedic Diseases Treatment.

Musculoskeletal disorders (MSDs) are conditions that can affect muscles, bones, and joints. These disorders are very painful and severely limit patients' mobility and are more common in the elderly. MSCs are multipotent stem cells isolated from embryonic (such as the umbilical cord) and mature sources (such as adipose tissue and bone marrow). These cells can differentiate into various cells such as osteoblasts, adipocytes, chondrocytes, NP-like cells, Etc. Due to MSC characteristics such as immunomodulatory properties, ability to migrate to the site of injury, recruitment of cells involved in repair, production of growth factors, and large amount production of extracellular vesicles, these cells have been used in many regenerative-related medicine studies. Also, MSCs produce different types of EVs, such as exosomes, to the extracellular environment. Exosomes reflect MSCs' characteristics and do not have cell therapy-associated problems because they are cell-free. These vesicles carry proteins, nucleic acids, and lipids to the host cell and change their function. This review focuses on MSCs and MSCs exosomes' role in repairing dense connective tissues such as tendons, cartilage, invertebrate disc, bone fracture, and osteoporosis treatment.

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.

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.

Prealbumin Correlates with C-reactive Protein in Rheumatic Musculoskeletal Diseases.

OBJECTIVE: Prealbumin is a blood component tested for nutrition monitoring, which could be affected during inflammation. This study aimed to investigate the relationships between prealbumin and C-reactive protein (CRP) in inflammatory rheumatic musculoskeletal diseases (RMDs), including Takayasu arteritis, antineutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, Behcet's disease and polymyositis/dermatomyositis. METHODS: A total of 52 healthy controls and 508 RMD patients were included. We collected 3714 clinical and laboratory records from June 2011 to August 2019, and the longest follow-up period was eleven years. The associations between prealbumin and CRP, the globulin gap, the albumin-to-globulin ratio, and IgG were evaluated. RESULTS: Prealbumin had a high correlation coefficient (r=-0.497, P<0.001), consistent changes over time with CRP, and a high area under the curve [AUC=0.777 (95% CI 0.76-0.795)] for CRP. The statistical relationship between the prealbumin and CRP was not affected by sex, ethnicity or age. Among RMDs, prealbumin showed the strongest correlation with CRP in Takayasu arteritis (r=0.607, P<0.001). In addition, a moderate relationship was observed between prealbumin and IgG, the globulin gap and the albumin-to-globulin ratio. CONCLUSION: Prealbumin is closely related to CRP in Chinese patients with five chronic inflammatory RMDs, which may be due to the influence of chronic inflammation during the course of disease.

Oxygen-Ozone Therapy in the Rehabilitation Field: State of the Art on Mechanisms of Action, Safety and Effectiveness in Patients with Musculoskeletal Disorders.

In recent years, the interest in oxygen-ozone (O2O3) therapy application has considerably increased in the field of rehabilitation. Despite its widespread use in common clinical practice, the biochemical effects of O2O3 are still far from being understood, although its chemical properties seem to play a pivotal role in exerting its positive effects on different pathological conditions. Indeed, the effectiveness of O2O3 therapy might be partly due to the moderate oxidative stress produced by O3 interactions with biological components. O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune over-activation, and most musculoskeletal disorders share these pathophysiological processes. The present comprehensive review depicts the state-of-the-art on the mechanisms of action, safety and effectiveness of O2O3 therapy in the complex scenario of the management of musculoskeletal disorders. Taken together, our findings suggest that O2O3 therapy seems to reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis, as reported by several studies in the literature. However, to date, further studies are warranted to clearly investigate the therapeutic effects of this promising therapy on other musculoskeletal disorders in the field of rehabilitation.

Applications of Lipidomics to Age-Related Musculoskeletal Disorders.

PURPOSE OF REVIEW: The goal of this review is to highlight the need for new biomarkers for the diagnosis and treatment of musculoskeletal disorders, especially osteoporosis and sarcopenia. These conditions are characterized by loss of bone and muscle mass, respectively, leading to functional deterioration and the development of disabilities. Advances in high-resolution lipidomics platforms are being used to help identify new lipid biomarkers for these diseases. RECENT FINDINGS: It is now well established that bone and muscle have important endocrine functions, including the release of bioactive factors in response to mechanical and biochemical stimuli. Bioactive lipids are a prominent set of these factors and some of these lipids are directly related to the mass and function of bone and muscle. Recent lipidomics studies have shown significant dysregulation of lipids in aged muscle and bone, including alterations in diacylglycerols and ceramides. Studies have shown that alterations in some types of plasma lipids are associated with aging including reduced bone mineral density and the occurrence of osteoporosis. Musculoskeletal disorders are a major burden in our society, especially for older adults. The development and application of new lipidomics methods is making significant advances in identifying new biomarkers for these diseases. These studies will not only lead to improved detection, but new mechanistic insights that could lead to new therapeutic targets and interventions.

Biomarkers and Nutrients in Musculoskeletal Disorders.

Worldwide, the burden of musculoskeletal disorders is increasing with great variations between-countries, which makes it difficult for policymakers to provide resources and adequate interventions in order to provide for their appropriate management [...].

The muscle to bone axis (and viceversa): An encrypted language affecting tissues and organs and yet to be codified?

Skeletal muscles and bone tissue form the musculoskeletal apparatus, a complex system essential for the voluntary movement. The loss of muscle mass and muscle strength is often associated with a loss of bone mass, in a "hazardous duet" which implies the co-existence of sarcopenia-osteoporosis and exposes patients to a deterioration in quality of life and increased mortality. From the mechanostat theory to the recent definition of the osteosarcopenia syndrome, many aspects of muscle-bone interaction have been investigated in recent decades. The mechanical interaction is now accepted, considering the close anatomical relationship between the two tissues, however, much remains to be discovered regarding the biochemical muscle-bone interaction. Skeletal muscle has been defined as an endocrine organ capable of exerting an action on other tissues. Myokines, bioactive polypeptides released by the muscle, could represent the encrypted message in the communication between muscle and bone. These two tissues have a reciprocal influence on their metabolisms and respond in a similar way to the multiple external factors. The aim of this review is to stimulate the understanding of the encrypted language between muscle and bone, highlighting the role of catabolic pathways and oxidative stress in the musculoskeletal apparatus to elucidate the shared mechanisms and the similarity of response to the same stimuli by different tissues. Our understanding of muscle-bone interactions it could be useful to identify and develop new strategies to treat musculoskeletal diseases, together with pharmacological, nutritional and exercise-based approaches, which are already in use for the treatment of these pathologies.