PRDM family proteins are a group of epigenetic regulators characterized by a conserved PR domain and multiple zinc-finger motifs. To date, eighteen PRDM family members have been identified in both mice and humans. Increasing evidence indicates that PRDM members play critical roles in the regulation of immune responses and immune-related diseases. They are involved in key processes such as hematopoiesis, immune cell differentiation, inflammatory signaling, and immunometabolic regulation. Dysregulation of PRDM proteins has been associated with a variety of pathological conditions, including hematological malignancies, autoimmune and inflammatory diseases, and metabolic disorders. Notably, functional studies of PRDM family members remain highly uneven, with a few proteins extensively characterized while many others are still poorly understood. This review summarizes recent advances in the structural features and biological functions of PRDM proteins, with a particular focus on their roles in immune regulation and endocrine-metabolic homeostasis. Furthermore, we discuss their involvement in disease pathogenesis and highlight their potential as therapeutic targets. Overall, this work provides a systematic overview of PRDM family functions and offers insights for future research in immune-mediated and metabolic diseases.

The PRDM (PR domain-containing) family consists of transcriptional regulators characterized by a PR (PRDI-BF1 and RIZ homology) domain, a subtype of the SET domain, and a variable number of zinc finger motifs. Nineteen PRDM family members have been identified in both mice and humans, and increasing evidence supports their roles as epigenetic regulators in development and disease. PRDM proteins share a conserved structure, comprising an N-terminal PR domain with potential histone methyltransferase activity and C-terminal C2H2-type zinc fingers involved in protein–protein, protein–RNA, and protein–DNA interactions. Recent studies indicate that multiple PRDM family members are involved in the regulation of the neuro-motor system, including neural lineage specification, neuronal differentiation, motor function maintenance, and neuromuscular-related pathological processes. This review summarizes current evidence on the functions and regulatory mechanisms of PRDM family members in the neuro-motor system. Overall, PRDM family members act as important epigenetic regulators in the neuro-motor system. Clarifying their molecular mechanisms may contribute to a better understanding of neuro-motor regulation and provide a theoretical basis for future research in exercise and movement science.

Exosomes derived from various cellular sources play a pivotal role in mediating and regulating bone and cartilage regeneration for conditions such as bone defects, fractures, cartilage repair, osteoporosis, and osteoarthritis. As essential intercellular communication vehicles, exosomes transmit long non-coding RNAs (lncRNAs) to modulate cellular behaviors in the bone microenvironment, which has been a central focus of contemporary research.This review consolidates existing evidence on exosome-derived lncRNAs in bone remodeling, revealing their regulatory roles through signaling pathway networks on osteoclasts, osteoblasts, and related bone/cartilage lineage cells, including mesenchymal stem cells, chondrocytes, and osteoclasts. Exosome-encapsulated lncRNAs that regulate osteogenic differentiation of bone marrow mesenchymal stem cells, osteoclast activity, bone-vascular coupling, and bone metastasis show promise as minimally invasive biomarkers for diagnosis, risk stratification, and therapeutic monitoring of bone metabolic disorders. Moreover, harnessing exosomes as natural, engineerable delivery vehicles can advance the development of bone-targeted, precise, and low-toxicity therapeutic strategies to complement existing pharmacologic and regenerative treatments.

The growth period represents a crucial bone mass acquisition and skeletal development phase. During this stage, bone tissues exhibit remarkable resilience and high plasticity, thereby laying a robust foundation for optimal bone strength. Growing bones are highly responsive to external stimuli, particularly exercise and mechanical loading. Appropriate physical activity or mechanical stimulation facilitates the attainment of peak bone mass and offers long-term protection against bone diseases. Therefore, exploring how exercise and mechanical stimuli influence bone development during this critical period and their underlying mechanisms is essential. This study provides a comprehensive review of the effects of exercise and mechanical stimulation on bone development and growth during the growth period. In particular, it focuses on the state of bone cells, such as bone marrow mesenchymal stem cells, osteoblasts, chondrocytes, osteoclasts, and osteocytes, and the molecular mechanisms governing mechanoregulation. Additionally, this study delves into the signaling pathways influenced by exercise and mechanical stimuli, including Wnt/β-catenin, bone morphogenetic protein/SMAD proteins, phosphatidylinositol 3-kinase/protein kinase, receptor activator of nuclear factor κB-receptor activator of nuclear factor κB ligand-osteoprotegerin, and mitogen-activated protein kinase. These pathways are pivotal in regulating bone formation, resorption, and remodeling. This study also analyzes the impact of exercise-modulated signaling pathways on bone development in children and adolescents to provide theoretical insights and practical guidance for designing scientifically sound exercise programs. Ultimately, these findings contribute to optimizing bone health strategies during youth, maintaining long-term bone health, and reducing the risk of bone-related disorders later in life.

Osteopontin (OPN), encoded by the SPP1/Spp1 gene, is increasingly recognized as an extracellular matrix-associated immunoregulatory molecule in the central nervous system (CNS). In CNS-related contexts, OPN does not act as a uniformly protective or detrimental factor. Instead, its effects depend on the producing cell type, molecular form, receptor axis, disease stage, and lesion compartment. Accumulating evidence indicates that OPN may participate in reparative processes, including tissue preservation, debris clearance, vascular remodeling, and support of myelin-related repair, while sustained or ectopic OPN activity may contribute to synaptic injury, persistent glial reactivity, remyelination failure, and immunosuppressive tumor progression. In this review, we summarize the molecular basis of SPP1/Spp1 expression and OPN protein signaling, with emphasis on isoforms, proteolytic processing, receptor usage, and secreted versus intracellular OPN. We then discuss its roles in CNS development, chronic neurological diseases, acute CNS injury, and neuro-oncology, and highlight the need to distinguish biomarker associations, omics-based candidate pathways, and functionally validated mechanisms when considering OPN-related diagnostic or therapeutic strategies.

Transcranial direct current stimulation (tDCS) and transcutaneous electrical nerve stimulation (TENS) are both recognized for their analgesic effects; however, evidence suggests limitations in their efficacy when applied to knee osteoarthritis (KOA) after stroke. This study aimed to assess the efficacy and cortical activity impact of a dual-target electrical stimulation approach combining tDCS and TENS in the treatment of KOA after stroke. We hypothesized that the combination of tDCS with TENS could more effectively address KOA after stroke by enhancing brain activity through the induction of neural oscillations. To test this hypothesis, a double-blind, randomized trial was conducted with 30 participants receiving either TENS + tDCS or TENS + sham tDCS over an 8-week period, from Monday to Friday. Electroencephalograms (EEGs), Brief Pain Inventory (BPI), visual analog scale (VAS), stride length, cadence, 6-min walk test (6 MWT), knee range of motion (ROM), and quadriceps strength were collected pre- and poststimulation. Pain indicators were analyzed using t-tests for continuous variables and chi-square tests for categorical variables, with repeated measures ANOVA employed to explore changes and interactions over time. For EEG analysis, paired t-tests were utilized to investigate changes in brain regions before and after treatment on the affected side, with visual analysis conducted subsequently. The results indicated that the combined treatment led to significant improvements in the affected hemisphere, with significant changes observed in α1, α2, and β power. Additionally, significant group× time interaction effects were noted for BPI, VAS, stride length, cadence, and 6MWT. The study concludes that dual-target electrostimulation using tDCS combined with TENS significantly ameliorates knee joint inflammation following stroke by acting on the cerebral cortex and target organs. Trial Registration: Chinese Clinical Trial Registry: ChiCTR2200064735.

BACKGROUND:Hyperuricemia (HUA) is an independent risk factor for chronic kidney disease (CKD) and can lead to hyperuricemic nephropathy (HN) with skeletal disorders and bone loss. Exercise, as a non-pharmacologic intervention, has potential value in improving bone health and slowing disease progression. However, the protective effect of exercise on HN-induced bone loss and its mechanism has not been clarified. This study aims to investigate the effects of moderate-intensity exercise on renal injury and bone microstructure in HN mice. METHOD:Thirty-two 5-week-old C57BL/6 mice were randomly divided into blank control (CON), model (HUA), exercise blank control (EX-CON), and exercise model (EX-HUA) groups. The HN model was induced by gavage of potassium oxalate (300 mg/kg) and adenine (75 mg/kg) in the HUA and EX-HUA groups. The EX-CON and EX-HUA groups were subjected to 8 weeks of moderate-intensity exercise. At the end of the experiment, serum levels of uric acid, creatinine, and urea nitrogen, as well as inflammatory factors and uric acid excretion factors in renal tissues, were detected, and then the pathological changes in the kidneys were assessed by HE staining, and the microstructures of the bones were assessed and analyzed by micro-CT, HE staining and TRAP staining. The expression of osteogenic factors (ALP, RUNX2) and bone resorption factors (MMP9, NFATC1) were detected by qPCR, Western blotting, and immunofluorescence. RESULT:Compared with the CON group, mice in the HUA group showed significantly higher serum uric acid levels, lower levels of creatinine and urea nitrogen, and pathological changes in the kidneys, such as vacuolar degeneration, nuclear detachment, and tubular atrophy. After the exercise intervention, the uric acid level of the EX-HUA group was significantly reduced, the renal function indexes were improved, and the renal pathological damage was reduced. Micro-CT results showed that the bone quality, bone density, trabecular tissue volume, trabecular number, trabecular connectivity, and trabecular thickness of the HUA group were significantly decreased, and trabecular separation was increased, whereas the exercise intervention significantly improved these bone microstructural parameters. In addition, the mRNA and protein expression levels of bone-forming factors (ALP, RUNX2) were significantly reduced in the HUA group, while the expression levels of bone resorption factors (MMP9, NFATC1) were significantly increased, and exercise intervention reversed these changes. CONCLUSION:hyperuricemic nephropathy leads to deterioration of bone microarchitecture, dysregulation of the balance between bone formation and bone resorption, and consequent bone loss. In contrast, moderate-intensity exercise improves renal function and regulates the balance of osteogenic-osteoclastogenic cytokines, thereby attenuating renal injury and bone loss in hyperuricemic nephropathy mice.

In recent years, the bidirectional regulatory mechanism of the bone-brain axis has become a hotspot for interdisciplinary research. In this paper, we systematically review the anatomical and functional links between bone and the central nervous system, focusing on the regulation of brain function by bone-derived signals and their clinical translational potential. At the anatomical level, the blood–brain barrier permeability mechanism and the unique structure of the periventricular organs establish the anatomical basis for bone-brain information transmission. Innovative discoveries indicate that the bone cell network (bone marrow mesenchymal stem cells, osteoblasts, osteoclasts, and bone marrow monocytes) directly regulates neuroplasticity and the inflammatory microenvironment through the secretion of factors such as osteocalcin, lipid transporter protein 2, nuclear factor κB receptor-activating factor ligand, and fibroblast growth factor 23, as well as exosome-mediated remote signaling. Clinical studies have revealed a bidirectional vicious cycle between osteoporosis and Alzheimer’s disease: reduced bone density exacerbates Alzheimer’s disease pathology through pathways such as PDGF-BB, while AD-related neurodegeneration further accelerates bone loss. The breakthrough lies in the discovery that anti-osteoporotic drugs, such as bisphosphonates, improve cognitive function. In contrast, neuroactive drugs modulate bone metabolism, providing new strategies for the treatment of comorbid conditions. Additionally, whole-body vibration therapy shows potential for non-pharmacological interventions by modulating bone-brain interactions through the mechano-osteoclast signaling axis. In the future, it will be essential to integrate multiple groups of biomarkers to develop early diagnostic tools that promote precise prevention and treatment of bone-brain comorbidities. This article provides a new perspective on the mechanisms and therapeutic strategies of neuroskeletal comorbidities.

Bone is a highly calcified and vascularized tissue. The vascular system plays a vital role in supporting bone growth and repair, such as the provision of nutrients, growth factors, and metabolic waste transfer. Moreover, the additional functions of the bone vasculature, such as the secretion of various factors and the regulation of bone-related signaling pathways, are essential for maintaining bone health. In the bone microenvironment, bone tissue cells play a critical role in regulating angiogenesis, including osteoblasts, bone marrow mesenchymal stem cells (BMSCs), and osteoclasts. Osteogenesis and bone angiogenesis are closely linked. The decrease in osteogenesis and bone angiogenesis caused by aging leads to osteoporosis. Long noncoding RNAs (lncRNAs) are involved in various physiological processes, including osteogenesis and angiogenesis. Recent studies have shown that lncRNAs could mediate the crosstalk between angiogenesis and osteogenesis. However, the mechanism by which lncRNAs regulate angiogenesis‒osteogenesis crosstalk remains unclear. In this review, we describe in detail the ways in which lncRNAs regulate the crosstalk between osteogenesis and angiogenesis to promote bone health, aiming to provide new directions for the study of the mechanism by which lncRNAs regulate bone metabolism.

Research findings reveal that thermal environments precisely regulate the skeletal system through a triple regulation of “structural morphology-cellular dynamics-molecular mechanisms”: At the tissue morphology level, moderate heat exposure can promote increased bone density and longitudinal growth, as well as improved fracture load and yield point, but may negatively affect geometric shape and cortical bone thickness. Continuous high-temperature exposure harms bone structure, manifested as changes in biomechanical characteristics such as decreased toughness and rigidity. At the cellular level, thermal environments directly affect the proliferation/apoptosis balance of osteoblasts and osteoclasts, and by regulating osteocyte network activity and bone marrow mesenchymal stem cell fate decisions, these four cell populations form temperature-dependent metabolic regulatory circuits. At the molecular dimension, heat stress can activate the release of neural factors such as CGRP and NPY, which possess dual regulatory functions promoting both bone formation and resorption; simultaneously achieving coordinated regulation of angiogenesis and fat inhibition through VEGF and TGFβ. The thermal environment–bone regulatory mechanisms revealed in this study have important translational value: they not only provide theoretical basis for biomechanical protection strategies for high-temperature workers and athletes, but also offer innovative entry points for analyzing the pathological mechanisms of heat stroke secondary bone injury and osteoporosis through heat stress-related signaling pathways, while establishing a theoretical foundation for the development of temperature-responsive functionalized biomaterials in bone tissue engineering.

Traumatic brain injury (TBI), which refers to damage caused by external forces to the brain, significantly affects systemic organs and tissues, especially bone homeostasis. An increasing number of studies have revealed bidirectional crosstalk between the brain and bone, and the interactions between these systems in the context of TBI remain unclear. Here, existing research on the relationship between the brain and bone is summarized to explore their interactions and underlying mechanisms in TBI. Clinical studies indicate that long-term loss of bone mass and increased risk of osteoporosis occur in patients after TBI. Interestingly, the rate of bone healing is accelerated when patients with TBI also suffer from fractures, which then worsens the prognosis of TBI. The bidirectional effects and underlying mechanisms that connect TBI and bone through neurohormones, neuropeptides, neurotransmitters, and mechanical factors are reviewed. The promising applications of bone marrow mesenchymal stromal cells, their derived extracellular vesicles, and bone-derived factors for TBI recovery are also elucidated. Strategies to prevent osteoporosis management and potential mechanisms to accelerate fracture healing after TBI are proposed based on the brain-bone axis, and results are expected to translate into a clinical scenario for TBI and bone disease.

PR/SET domain 2 (PRDM2)/RIZ is a member of the histone/protein methyltransferases (PRDMs) superfamily. Discovered to have the ability to bind retinoblastoma in the mid-1990s, PRDM2 was assumed to play a role in neuronal development. Like other family members characterized by a conserved N-terminal PR structural domain and a classical C2H2 zinc-finger array at the C-terminus, PRDM2 encodes two major protein types, the RIZ1 and RIZ2 isoforms. The two subtypes differ in the presence or absence of the PR domain: the RIZ1 subtype has the PR domain, whereas the RIZ2 subtype lacks it. The PR domain exhibits varying conservation levels across species and shares structural and functional similarities with the catalytic SET domain, defining histone methyltransferases. Functioning as an SET domain, the PR domain possesses protein-binding interfaces and acts as a lysine methyltransferase. The variable number of classic C2H2 zinc fingers at the C-terminus may mediate protein–protein, protein–RNA, or protein–DNA interactions. An imbalance in the RIZ1/RIZ2 mechanism may be an essential cause of malignant tumors, where PR-positive isoforms are usually lost or downregulated. Conversely, PR-negative isoforms are always present at higher levels in cancer cells. RIZ1 isoforms are also important targets for estradiol interaction with hormone receptors. PRDM2 can regulate gene transcription and expression combined with transcription factors and plays a role in the development of several systemic diseases through mRNA expression deletion, code-shift mutation, chromosomal deletion, and missense mutation occurrence. Thus, PRDM2 is a key indicator for disease diagnosis, but it lacks systematic summaries to serve as a reference for study. Therefore, this paper describes the structure and biological function of PRDM2 from the perspective of its role in various systemic diseases. It also organizes and categorizes its latest research progress to provide a systematic theoretical basis for a more in-depth investigation of the molecular mechanism of PRDM2’s involvement in disease progression and clinical practice.

With the advancement of global population aging, the incidence of skeletal diseases (e.g. osteoporosis, fractures, and osteoarthritis) in clinical diagnosis increases and poses a serious threat to human health. Skeletal diseases usually occur as a result of disturbed cellular metabolism in a specific period or environment. The bone microenvironment, as an important physiological environment of bone tissue, consists of various cell types, and cell-cell interactions play a decisive role in the biological behavior and metabolic regulation of bone cells. Disorders of the bone microenvironment can exacerbate bone diseases. Conventional therapeutic for skeletal diseases often suffer from poor efficacy, low targeting, and side effects. Therefore, a new therapeutic strategy should be developed urgently to improve the existing deficiencies. With the continuous advancement of nanomedicine, the application of nanomaterials provides new research perspectives and application value for the treatment of skeletal diseases. With their unique physicochemical properties, nanomaterials can directly or indirectly mediate the bone microenvironment to regulate the bone metabolic process through self-regulation, drug carriers, and in vivo scaffolds. All the above strategies are extensively explored in this study. In this paper, we systematically summarize the nanomaterials currently used in the clinical treatment of bone diseases and discuss the application strategies of nanomaterials to regulate the bone microenvironment and thus bone metabolism. Moreover, we evaluated the challenges faced by nanomaterials in the clinical treatment of bone diseases. We aim to provide basic theories and new perspectives for the design and development of novel nanomaterials for improved clinical applications.

Hyperbaric oxygen therapy (HBOT) is a therapeutic modality that enhances tissue oxygenation by delivering 100% oxygen at pressures greater than 1 absolute atmosphere. In recent years, HBOT has shown considerable potential in the treatment of bone diseases. While excess oxygen was once thought to induce oxidative stress, recent studies indicate that when administered within safe limits, HBOT can notably promote bone healing and repair. Extensive basic research has demonstrated that HBOT can stimulate the proliferation and differentiation of osteoblasts and encourage bone angiogenesis. Furthermore, HBOT has been shown to exert a beneficial influence on bone metabolism by modulating the inflammatory response and redox status. These mechanisms are closely related to core issues of bone biology. Specifically, in the context of fracture healing, bone defect repair, and conditions such as osteoporosis, HBOT targets the key bone signaling pathways involved in bone health, thereby exerting a therapeutic effect. Several clinical studies have demonstrated the efficacy of HBOT in improving bone health. However, the optimal HBOT regimen for treating various bone diseases still requires further definition to expand the indications for its clinical application. This paper outlines the mechanisms of HBOT, focusing on its antioxidant stress, promotion of bone vascularization, and anti-inflammatory properties. The paper also describes the application of HBOT in orthopedic diseases, thereby providing a scientific basis for the development of precise and personalized HBOT treatment regimens in clinical orthopedics.

Skeletal muscles and bones maintain musculoskeletal system function through their collaborative interaction, whereby muscles regulate bone metabolism via mechanical coupling. An increasing number of studies have shown that various cytokines secreted by skeletal muscles during exercise closely regulate the balance of bone homeostasis. Interleukin-6 (IL-6), one of the first muscle-secreted factors to be discovered, not only plays an important role in regulating the function of the muscle itself but also regulates bone metabolic processes in a bidirectional manner through multiple complex signal transduction pathways, thereby affecting the balance between bone formation and bone resorption. The exact mechanism by which IL-6 regulates bone metabolism is not fully understood, and there are few summaries on how exercise affects bone metabolism through IL-6 from skeletal muscles. Accordingly, this study will take skeletal muscle-derived IL-6 as an entry point to explore how the cross-organ regulatory activities of the muscles targeting bones during exercise affect bone metabolic processes. This study also aims to improve the mechanism of muscle–bone crosstalk under the effect of exercise and provide a theoretical basis and clinical diagnosis and treatment ideas from multiple perspectives for exercise to improve bone health.

Fatigue is not only a widespread subjective experience but also a complex physiological and pathological state involving multiple organs and systems. Currently, there is no consensus on the definition and classification of fatigue. Based on its causes, this paper categorizes fatigue into sports fatigue, occupational fatigue, and pathological fatigue. It elaborates on the specific manifestations and underlying mechanisms of fatigue in the motor, nervous, cardiovascular, digestive, urinary, endocrine, and reproductive systems, aiming to uncover the intrinsic connections of fatigue phenotypes across different systems. These findings may provide key targets for gene-assisted therapy of fatigue-related complications, thereby establishing a new theoretical foundation for the clinical management of fatigue and related research.

Osteoarthritis (OA) is a chronic degenerative joint disease with multiple causative factors such as aging, mechanical injury, and obesity. Autophagy is a complex dynamic process that is involved in the degradation and modification of intracellular proteins and organelles under different pathophysiological conditions. Autophagy, as a cell survival mechanism under various stress conditions, plays a key role in regulating chondrocyte life cycle metabolism and cellular homeostasis. Non-coding RNAs (ncRNAs) are heterogeneous transcripts that do not possess protein-coding functions, but they can act as effective post-transcriptional and epigenetic regulators of gene and protein expression, thus participating in numerous fundamental biological processes. Increasing evidence suggests that ncRNAs, autophagy, and their crosstalk play crucial roles in OA pathogenesis. Therefore, we summarized the complex role of autophagy in OA chondrocytes and focused on the regulatory role of ncRNAs in OA-associated autophagy to elucidate the complex pathological mechanisms of the ncRNA-autophagy network in the development of OA, thus providing new research targets for the clinical diagnosis and treatment of OA.

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.

Urologic oncology is a significant public health concern on a global scale. Recent research indicates that long chain non-coding RNAs (lncRNAs) and autophagy play crucial roles in various cancers, including urologic malignancies. This article provides a summary of the latest research findings, suggesting that lncRNA-mediated autophagy could either suppress or promote tumors in prostate, kidney, and bladder cancers. The intricate network involving different lncRNAs, target genes, and mediated signaling pathways plays a crucial role in urological malignancies by modulating the autophagic process. Dysregulated expression of lncRNAs can disrupt autophagy, leading to tumorigenesis, progression, and enhanced resistance to therapy. Consequently, targeting particular lncRNAs that control autophagy could serve as a dependable diagnostic tool and a promising prognostic biomarker in urologic oncology, while also holding potential as an effective therapeutic approach.