Therapeutic potential of mesenchymal stem cell-derived exosomes in skeletal diseases

Skeletal diseases impose a considerable burden on society. The clinical and tissue-engineering therapies applied to alleviate such diseases frequently result in complications and are inadequately effective. Research has shifted from conventional therapies based on mesenchymal stem cells (MSCs) to exosomes derived from MSCs. Exosomes are natural nanocarriers of endogenous DNA, RNA, proteins, and lipids and have a low immune clearance rate and good barrier penetration and allow targeted delivery of therapeutics. MSC-derived exosomes (MSC-exosomes) have the characteristics of both MSCs and exosomes, and so they can have both immunosuppressive and tissue-regenerative effects. Despite advances in our knowledge of MSC-exosomes, their regulatory mechanisms and functionalities are unclear. Here we review the therapeutic potential of MSC-exosomes for skeletal diseases

The critical role of TRIM protein family in intervertebral disc degeneration: mechanistic insights and therapeutic perspectives

Intervertebral disc degeneration (IVDD) is a leading cause of chronic back pain, contributing significantly to reduced quality of life and global public health burdens. The TRIM (Tripartite Motif-containing) protein family, with its diverse regulatory roles, has emerged as a key player in critical cellular processes such as inflammation, cell death, and extracellular matrix (ECM) metabolism. Recent findings underscore the involvement of TRIM proteins in IVDD pathogenesis, where they regulate stress responses, maintain cellular homeostasis, and influence the functional integrity of nucleus pulposus (NP) and annulus fibrosus (AF) cells. This review explores the multifaceted roles of TRIM proteins in IVDD, highlighting their contributions to pathological pathways and their potential as therapeutic targets. Advancing our understanding of TRIM protein-mediated mechanisms may pave the way for innovative and precise therapeutic strategies to combat IVDD

Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family

Abstract Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated.Abstract Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated

Expression and Biological Functions of miRNAs in Chronic Pain: A Review on Human Studies

none10noChronic pain is a major public health problem and an economic burden worldwide. However, its underlying pathological mechanisms remain unclear. MicroRNAs (miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate gene expression and serve key roles in physiological and pathological processes. This review aims to synthesize the human studies examining miRNA expression in the pathogenesis of chronic primary pain and chronic secondary pain. Additionally, to understand the potential pathophysiological impact of miRNAs in these conditions, an in silico analysis was performed to reveal the target genes and pathways involved in primary and secondary pain and their differential regulation in the different types of chronic pain. The findings, methodological issues and challenges of miRNA research in the pathophysiology of chronic pain are discussed. The available evidence suggests the potential role of miRNA in disease pathogenesis and possibly the pain process, eventually enabling this role to be exploited for pain monitoring and management.Sabina S.; Panico A.; Mincarone P.; Leo C.G.; Garbarino S.; Grassi T.; Bagordo F.; De Donno A.; Scoditti E.; Tumolo M.R.Sabina, S.; Panico, A.; Mincarone, P.; Leo, C. G.; Garbarino, S.; Grassi, T.; Bagordo, F.; De Donno, A.; Scoditti, E.; Tumolo, M. R

Role of signaling pathways in age-related orthopedic diseases: focus on the fibroblast growth factor family

Fibroblast growth factor (FGF) signaling encompasses a multitude of functions, including regulation of cell proliferation, differentiation, morphogenesis, and patterning. FGFs and their receptors (FGFR) are crucial for adult tissue repair processes. Aberrant FGF signal transduction is associated with various pathological conditions such as cartilage damage, bone loss, muscle reduction, and other core pathological changes observed in orthopedic degenerative diseases like osteoarthritis (OA), intervertebral disc degeneration (IVDD), osteoporosis (OP), and sarcopenia. In OA and IVDD pathologies specifically, FGF1, FGF2, FGF8, FGF9, FGF18, FGF21, and FGF23 regulate the synthesis, catabolism, and ossification of cartilage tissue. Additionally, the dysregulation of FGFR expression (FGFR1 and FGFR3) promotes the pathological process of cartilage degradation. In OP and sarcopenia, endocrine-derived FGFs (FGF19, FGF21, and FGF23) modulate bone mineral synthesis and decomposition as well as muscle tissues. FGF2 and other FGFs also exert regulatory roles. A growing body of research has focused on understanding the implications of FGF signaling in orthopedic degeneration. Moreover, an increasing number of potential targets within the FGF signaling have been identified, such as FGF9, FGF18, and FGF23. However, it should be noted that most of these discoveries are still in the experimental stage, and further studies are needed before clinical application can be considered. Presently, this review aims to document the association between the FGF signaling pathway and the development and progression of orthopedic diseases. Besides, current therapeutic strategies targeting the FGF signaling pathway to prevent and treat orthopedic degeneration will be evaluated

Insights into the Notch signaling pathway in degenerative musculoskeletal disorders: Mechanisms and perspectives

Abstract Degenerative musculoskeletal disorders are a group of age-related diseases of the locomotive system that severely affects the patient's ability to work and cause adverse sequalae such as fractures and even death. The incidence and prevalence of degenerative musculoskeletal disorders is rising owing to the aging of the world’s population. The Notch signaling pathway, which is expressed in almost all organ systems, extensively regulates cell proliferation and differentiation as well as cellular fate. Notch signaling shows increased activity in degenerative musculoskeletal disorders and retards the progression of degeneration to some extent. The review focuses on four major degenerative musculoskeletal disorders (osteoarthritis, intervertebral disc degeneration, osteoporosis, and sarcopenia) and summarizes the pathophysiological functions of Notch signaling in these disorders, especially its role in stem/progenitor cells in each disorder. Finally, a conclusion will be presented to explore the research and application of the perspectives on Notch signaling in degenerative musculoskeletal disorders.Abstract Degenerative musculoskeletal disorders are a group of age-related diseases of the locomotive system that severely affects the patient's ability to work and cause adverse sequalae such as fractures and even death. The incidence and prevalence of degenerative musculoskeletal disorders is rising owing to the aging of the world’s population. The Notch signaling pathway, which is expressed in almost all organ systems, extensively regulates cell proliferation and differentiation as well as cellular fate. Notch signaling shows increased activity in degenerative musculoskeletal disorders and retards the progression of degeneration to some extent. The review focuses on four major degenerative musculoskeletal disorders (osteoarthritis, intervertebral disc degeneration, osteoporosis, and sarcopenia) and summarizes the pathophysiological functions of Notch signaling in these disorders, especially its role in stem/progenitor cells in each disorder. Finally, a conclusion will be presented to explore the research and application of the perspectives on Notch signaling in degenerative musculoskeletal disorders

Investigating the regulation of the miR-199a-3p/TGF-β/Smad signaling pathway by BSHXF drug-containing serum combined with ADSCs for delaying intervertebral disc degeneration

BackgroundIntervertebral disc degeneration (IDD) significantly contributes to low back pain (LBP), yet effective treatment options are scarce. BSHXF, a classical traditional Chinese medicine formula, demonstrates dual pharmacological actions: tonifying kidneys, strengthening bones, activating blood circulation, and resolving stasis. It has been widely used in IDD management. Given its potential, combining BSHXF with miRNA regulation and stem cell therapy may enhance therapeutic outcomes by targeting molecular and cellular pathways underlying IDD pathogenesis.Aim of the studyIDD is recognized as one of the primary causes of low back pain, yet effective therapeutic interventions for this condition remain limited. This study explores the role of BSHXF drug-containing serum combined with adipose-derived stem cells (ADSCs) in slowing IDD progression via the miR-199a-3p/TGF-β/Smad signaling pathway. By comprehensively investigating the synergistic effects of this combination therapy, we aim to propose a novel multi-target strategy that addresses the complex pathogenesis of IDD.Materials and MethodsThis study employed a combination of in vivo and in vitro models. An IDD model was induced in rat caudal intervertebral discs through needle puncture, while an oxidative stress-induced ADSCs injury model was created in vitro using tert-butyl hydroperoxide (T-BHP). Cell viability was measured with the CCK-8 assay. Cell cycle distribution and mitochondrial reactive oxygen species (ROS) levels were assessed using flow cytometry. Cellular senescence was assessed using SA-β-galactosidase staining. Lactate dehydrogenase (LDH) activity was quantified to evaluate cellular damage. Differentiation into nucleus pulposus-like cells was assessed using immunofluorescence double staining for CD73 and COL2A1. ELISA was used to measure inflammatory cytokines (TNF-α, IL-1β, IL-4, IL-10) in cell supernatants. miR-199a-3p expression was determined using RT-qPCR. Western blotting was employed to quantify COL2A1, SOX9, and ACAN protein levels, reflecting nucleus pulposus-like differentiation and extracellular matrix (ECM) synthesis capacity. Western blotting was employed to assess pathway activity by analyzing the protein expressions of TGF-β1, Smad2, Smad3, and their phosphorylated forms, P-Smad2 and P-Smad3. In vivo experiments assessed histopathological degeneration through hematoxylin-eosin (HE) and Safranin O-Fast Green staining. Immunohistochemistry (IHC) analyzed COL1A1 and COL2A1 expression levels. RT-qPCR quantified miR-199a-3p expression. Western blotting was employed to assess the expression levels of TGF-β1, Smad2, Smad3, P-Smad2, and P-Smad3 for pathway regulation evaluation.ResultsOur experimental results demonstrated that serum containing BSHXF significantly alleviated T-BHP-induced oxidative stress, improved the cellular microenvironment, promoted ADSCs proliferation, and decelerated cellular senescence. Further mechanistic analysis revealed that BSHXF significantly activated the TGF-β/Smad signaling pathway, driving the differentiation of ADSCs into nucleus pulposus-like cells and restoring normal cell cycle progression. Overexpression of miR-199a-3p inhibited the TGF-β/Smad pathway, leading to ECM degradation and elevated expression of inflammatory factors (TNF-α, IL-1β). In contrast, BSHXF restored TGF-β/Smad pathway activity by downregulating miR-199a-3p expression. In vivo experiments demonstrated that miR-199a-3p overexpression exacerbated IDD, characterized by reduced COL2A1 expression, elevated COL1A1 levels, and increased disc fibrosis. BSHXF intervention markedly attenuated IDD progression by downregulating miR-199a-3p expression, reducing disc fibrosis, and effectively restoring collagen expression.ConclusionBSHXF activated the TGF-β/Smad pathway to promote the differentiation of ADSCs into nucleus pulposus-like cells. It exerted protective effects by alleviating oxidative stress damage, improving the microenvironment, delaying senescence, and enhancing cellular functions. This study is the first to reveal that miR-199a-3p overexpression exacerbates intervertebral disc fibrosis and degeneration. BSHXF restored TGF-β/Smad pathway activity by downregulating miR-199a-3p expression, thereby improving disc structure and function. This integrated approach offers a novel multi-target intervention strategy for IDD, demonstrating significant therapeutic potential

Role of the Inflammation-Autophagy-Senescence Integrative Network in Osteoarthritis

Osteoarthritis is the most common musculoskeletal disease causing chronic disability in adults. Studying cartilage aging, chondrocyte senescence, inflammation, and autophagy mechanisms have identified promising targets and pathways with clinical translatability potential. In this review, we highlight the most recent mechanistic and therapeutic preclinical models of aging with particular relevance in the context of articular cartilage and OA. Evidence supporting the role of metabolism, nuclear receptors and transcription factors, cell senescence, and circadian rhythms in the development of musculoskeletal system degeneration assure further translational efforts. This information might be useful not only to propose hypothesis and advanced models to study the molecular mechanisms underlying joint degeneration, but also to translate our knowledge into novel disease-modifying therapies for OA

Cuproptosis and its potential role in musculoskeletal disease

Cuproptosis, a recently identified form of copper-dependent cell death, arises from intracellular copper dyshomeostasis. As an essential trace element, copper plays a critical role in bioenergetic metabolism, redox regulation, and synaptic transmission. However, excessive copper exerts cytotoxic effects through multiple pathways, including increased reactive oxygen species (ROS) production, apoptotic cascade activation, necrotic membrane rupture, inflammatory responses, and mitochondrial dysfunction. Distinct from other cell death mechanisms, cuproptosis is characterized by copper ion binding to acetylated mitochondrial respiratory chain proteins, leading to pathogenic protein aggregation, iron-sulfur cluster depletion, and cellular collapse. Emerging evidence underscores aberrant copper accumulation and resultant proteotoxic stress as pivotal contributors to the pathogenesis of multiple musculoskeletal pathologies, including osteoporosis, osteoarthritis, sarcopenia, osteosarcoma, intervertebral disc degeneration, spinal cord injury, and biofilm-associated orthopedic infections. Understanding the spatiotemporal regulation of cuproptosis may provide novel opportunities for advancing diagnostic and therapeutic approaches in orthopedic medicine. This review synthesizes current insights into the molecular mechanisms of cuproptosis, its pathogenic role in musculoskeletal diseases, and the potential for biomarker-driven therapeutic interventions