Age-induced abnormalities in bone metabolism disrupt the equilibrium between bone resorption and formation. This largely stems from disturbances in bone homeostasis, in which signaling pathways exert a significant regulatory influence. Aging compromises the functionality of the bone marrow mesenchymal stem cells (BMSCs), ultimately resulting in tissue dysfunction and pathological aging. Age-related bone degradation primarily manifests as reduced bone formation and the increased accumulation of bone marrow fat. Cellular senescence diminishes bone cell vitality, thereby disrupting the balance of bone remodeling. Intensive osteoclast differentiation leads to the generation of more osteoclasts and increased bone resorption. This review provides insight into the impact of aging on bone, encompassing bone cell states during the aging process and bone signaling pathway transformations. It primarily delves into aging-related signaling pathways, such as the bone morphogenetic protein/Smad, Wnt/β-catenin, osteoprotegerin/receptor activator of NF-κB ligand/receptor activator of NF-κB, connexin43/miR21, and nuclear factor erythroid 2-related factor 2/antioxidant response element pathways, seeking to enhance our comprehension of crucial bone cells and their secretory phenotypes during aging. Furthermore, the precise molecular regulatory mechanisms underlying the interactions between bone signaling pathways and aging are investigated.

Aging is an inevitable physiological process, often accompanied by age-related bone loss and subsequent bone-related diseases that pose serious health risks. Research on skeletal diseases caused by aging in humans is challenging due to lengthy study durations, difficulties in sampling, regional variability, and substantial investment. Consequently, mice are preferred for such studies due to their similar motor system structure and function to humans, ease of handling and care, low cost, and short generation time. In this review, we present a comprehensive overview of the characteristics, limitations, applicability, bone phenotypes, and treatment methods in naturally aging mice and prematurely aging mouse models (including SAMP6, POLG mutant, LMNA, SIRT6, ZMPSTE24, TFAM, ERCC1, WERNER, and KL/KL-deficient mice). We also summarize the molecular mechanisms of these aging mouse models, including cellular DNA damage response, senescence-related secretory phenotype, telomere shortening, oxidative stress, bone marrow mesenchymal stem cell (BMSC) abnormalities, and mitochondrial dysfunction. Overall, this review aims to enhance our understanding of the pathogenesis of aging-related bone diseases.

With the aging of the global population, the incidence of musculoskeletal diseases has been increasing, seriously affecting people's health. As people age, the microenvironment within skeleton favors bone resorption and inhibits bone formation, accompanied by bone marrow fat accumulation and multiple cellular senescence. Specifically, skeletal stem/stromal cells (SSCs) during aging tend to undergo adipogenesis rather than osteogenesis. Meanwhile, osteoblasts, as well as osteocytes, showed increased apoptosis, decreased quantity, and multiple functional limitations including impaired mechanical sensing, intercellular modulation, and exosome secretion. Also, the bone resorption function of macrophage-lineage cells (including osteoclasts and preosteoclasts) was significantly enhanced, as well as impaired vascularization and innervation. In this study, we systematically reviewed the effect of aging on bone and the within microenvironment (including skeletal cells as well as their intracellular structure variations, vascular structures, innervation, marrow fat distribution, and lymphatic system) caused by aging, and mechanisms of osteoimmune regulation of the bone environment in the aging state, and the causal relationship with multiple musculoskeletal diseases in addition with their potential therapeutic strategy.

Bone is a tissue that is active throughout the lifespan, and its physiological activities, such as growth, development, absorption, and formation, are always ongoing. All types of stimulation that occur in sports play an important role in regulating the physiological activities of bone. Here, we track the latest research progress locally and abroad, summarize the recent, relevant research results, and systematically summarize the effects of different types of exercise on bone mass, bone strength and bone metabolism. We found that different types of exercise have different effects on bone health due to their unique technical characteristics. Oxidative stress is an important mechanism mediating the exercise regulation of bone homeostasis. Excessive high-intensity exercise does not benefit bone health but induces a high level of oxidative stress in the body, which has a negative impact on bone tissue. Regular moderate exercise can improve the body's antioxidant defense ability, inhibit an excessive oxidative stress response, promote the positive balance of bone metabolism, delay age-related bone loss and deterioration of bone microstructures and have a prevention and treatment effect on osteoporosis caused by many factors. Based on the above findings, we provide evidence for the role of exercise in the prevention and treatment of bone diseases. This study provides a systematic basis for clinicians and professionals to reasonably formulate exercise prescriptions and provides exercise guidance for patients and the general public. This study also provides a reference for follow-up research.

Osteopontin (OPN) is a multifunctional noncollagenous matrix phosphoprotein that is expressed both intracellularly and extracellularly in various tissues. As a growth regulatory protein and proinflammatory immunochemokine, OPN is involved in the pathological processes of many diseases. Recent studies have found that OPN is widely involved in the aging processes of multiple organs and tissues, such as T-cell senescence, atherosclerosis, skeletal muscle regeneration, osteoporosis, neurodegenerative changes, hematopoietic stem cell reconstruction, and retinal aging. However, the regulatory roles and mechanisms of OPN in the aging process of different tissues are not uniform, and OPN even has diverse roles in different developmental stages of the same tissue, generating uncertainty for the future study and utilization of OPN. In this review, we will summarize the regulatory role and molecular mechanism of OPN in different tissues and cells, such as the musculoskeletal system, central nervous system, cardiovascular system, liver, and eye, during senescence. We believe that a better understanding of the mechanism of OPN in the aging process will help us develop targeted and comprehensive therapeutic strategies to fight the spread of age-related diseases.

Exosomes are membranous lipid vesicles fused with intracellular multicellular bodies that are released into the extracellular environment. They contain bioactive substances, including proteins, RNAs, lipids, and cytokine receptors. Exosomes in the skeletal microenvironment are derived from a variety of cells such as bone marrow mesenchymal stem cells (BMSCs), osteoblasts, osteoclasts, and osteocytes. Their biological function is key in paracrine or endocrine signaling. Exosomes play a role in bone remodeling by regulating cell proliferation and differentiation. Genetic engineering technology combined with exosome-based drug delivery can therapy bone metabolic diseases. In this review, we summarized the pathways of exosomes derived from different skeletal cells (i.e., BMSCs, osteoblasts, osteocytes, and osteoclasts) regulate the skeletal microenvironment through proteins, mRNAs, and non-coding RNAs. By exploring the role of exosomes in the skeletal microenvironment, we provide a theoretical basis for the clinical treatment of bone-related metabolic diseases, which may lay the foundation to improve bone tumor microenvironments, alleviate drug resistance in patients.

The heart is the core organ of the circulatory system. Through the blood circulation system, it has close contact with all tissues and cells in the body. An exosome is an extracellular vesicle enclosed by a phospholipid bilayer. A variety of heart tissue cells can secrete and release exosomes, which transfer RNAs, lipids, proteins, and other biomolecules to adjacent or remote cells, mediate intercellular communication, and regulate the physiological and pathological activities of target cells. Cardiogenic exosomes play an important role in regulating almost all pathological and physiological processes of the heart. In addition, they can also reach distant tissues and organs through the peripheral circulation, exerting profound influence on their functional status. In this paper, the composition and function of cardiogenic exosomes, the factors affecting cardiogenic exosomes and their roles in cardiovascular physiology and pathophysiology are discussed, and the close relationship between cardiovascular system and motor system is innovatively explored from the perspective of exosomes. This study provides a reference for the development and application of exosomes in regenerative medicine and sports health, and also provides a new idea for revealing the close relationship between the heart and other organ systems.

Intervertebral disc (IVD) degeneration is considered to be the primary reason for low back pain (LBP), which has become more prevalent from 21 century, causing an enormous economic burden for society. However, in spite of remarkable improvements in the basic research of IVD degeneration (IVDD), the effects of clinical treatments of IVDD are still leaving much to be desired. Accumulating evidence has proposed the existence of endogenous stem/progenitor cells in the IVD that possess the ability of proliferation and differentiation. However, few studies have reported the biological properties and potential application of IVD progenitor cells in detail. Even so, these stem/progenitor cells have been consumed as a promising cell source for the regeneration of damaged IVD. In this review, we will first introduce IVD, describe its physiology and stem/progenitor cell niche, and characterize IVDSPCs between homeostasis and IVD degeneration. We will then summarize recent studies on endogenous IVDSPC-based IVD regeneration and exogenous cell-based therapy for IVDD. Finally, we will discuss the potential applications and future developments of IVDSPC-based repair of IVD degeneration.

Bone serves as the support for body and provide attachment points for the muscles. The musculoskeletal system is the basis for the human body to complete exercise. Studies believe that bone is not only the basis for constructing structures, but also participates in the regulation of organs outside bone. The realization of this function is closely related to the protein secreted by bone. Whether bone can realize their positions in the human body is also related to their secretion. Bone-derived proteins provide a medium for the targeted regulation of bones on organs, making the role of bone in human body more profound and concrete. Mechanical stimulation effects the extra-skeletal organs by causing quantitative changes in bone-derived factors. When bone receives mechanical stimulation, the nichle of bone responds, and the secretion of various factors changes. However, whether the proteins secreted by bone can interfere with disease requires more research. In this review article, we will first introduce the important reasons and significance of the in-depth study on bone-derived secretory proteins, and summarize the locations, structures and functions of these proteins. These functions will not only focus on the bone metabolism process, but also be reflected in the cross-organ regulation. We specifically explain the role of typical bone-derived secretory factors such as osteocalcin (OCN), osteopontin (OPN), sclerostin (SOST) and fibroblast growth factor 23 (FGF23) in different organs and metabolic processes, then establishing the relationship between them and diseases. Finally, we will discuss whether exercise or mechanical stimulation can have a definite effect on bone-derived secretory factors. Understanding their important role in cross-organ regulation is of great significance for the treatment of diseases, especially for the elderly people with more than one basic disease.

Exosomes are membranous lipid vesicles fused with intracellular multicellular bodies and then released into the extracellular environment. They contain various bioactive substances, including proteins, mRNA, miRNAs, lncRNAs, circRNAs, lipids, transcription factors, and cytokine receptors. Under certain conditions, bone marrow mesenchymal stem cells (BMSCs) can differentiate into osteoblasts, chondrocytes, adipocytes, and biological functions. This study provides a theoretical basis for the application of exosomes derived from bone marrow mesenchymal stem cells (BMSC-Exos) in osteology, exploring different sources of exosomes to improve bone microenvironment and resist bone metastasis. We also provided new ideas for the prevention and rehabilitation of human diseases by exosomes.