Search Results (121)

Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation into different cellular lineages, including adipocytes, chondrocytes, and osteocytes. This makes them strong candidates for repairing degenerative joint conditions such as osteoarthritis, in which native cartilage lacks repair capacity. The synovium is an attractive MSC source, with synovial MSCs demonstrating superior chondrogenic and proliferative potential compared to those from bone marrow or adipose tissue. The synovial joint is a heterogeneous environment, and MSCs can be isolated from the membrane, fluid, different histological subtypes of fibrous and adipose synovium, and different anatomical regions of synovium. This systematic review assesses whether MSCs from different synovial sources possess distinct properties. 2312 papers were identified, of which 10 met the inclusion and exclusion criteria and were included in the final review. Significant differences were identified in proliferation characteristics, immunophenotype and differentiation potential. Proximity to vasculature appeared to correlate with proliferation and differentiation potential, and MSCs from the synovial membrane may have superior proliferative characteristics compared to those from synovial fluid. More work is required to fully characterise these differences and understand their underlying molecular bases, but these findings may help inform the choice of MSC source for regenerative therapies. Full article

Liver fibrosis is a severe but common disease without an easy-to-access option for efficient treatment. Mesenchymal stem cells (MSCs) of different origins have been tested for antifibrotic effects in vitro, in vivo, and in clinical studies over the two last decades, although the comparative efficiency of different subtypes remains not fully understood, especially for long-term survival. In this study, we aimed to compare the long-time persistence of favorable effects in male Wistar rats with liver fibrosis treated using MSCs derived from white adipose tissue (AdMSCs) and bone marrow (BMSCs). Liver fibrosis was induced by carbon tetrachloride. We studied the survival rate; oxidative index, assessed via laser Doppler flowmetry; hepatic markers in blood plasma—albumin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; the ratio of liver to body mass; histological parameters—the number of adipocytes, lymphocytes, siderophages, and Ki67⁺ cells; and the relative areas of connective tissue proper and reticular fibers. Extra mortality was only typical for fibrotic animals subjected to the sham treatment in the first two weeks. Up to Day 270 of this study, both MSC-treated groups showed barely any differences from animals undergoing the sham treatment in terms of the oxidative index and blood markers, although AdMSC-treated rats presented a more favorable histological pattern than BMSC-treated ones, considering the relative area of reticular fibers and the Ki67 cell count. This study suggests that AdMSC treatments may be more appropriate than BMSC treatments in animal liver fibrosis models, with the results showing better potential for liver tissue regeneration 9 months after treatment. Full article

Background/Objectives: Osteoporosis poses significant obstacles as it causes an imbalance between osteoblasts and adipocytes, which results in the disruption of bone homeostasis. Although various magnesium-based scaffolds have been deployed for the treatment of osteoporotic bone defects, whether this can be achieved by alleviating bone–fat imbalance still requires further elucidation. Methods: We designed magnesium phosphate-based platforms (GMPCs), based on magnesium photopolymerized methacrylated gelatin (GelMA) and phosphate (K-struvite, MPC), and used them to deliver magnesium ions (Mg²⁺) for alleviating bone–fat imbalance locally. Results: The in vivo results demonstrated that the GMPCs not only improved osteogenic behavior at the implanted site, but also reduced the proportion of adipose tissues in a femoral defect model in 18-month-old SD rats. Moreover, by promoting the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts in a concentration-dependent manner, GMPCs significantly reduced adipogenic differentiation in vitro. Also, 5GMPC demonstrated the best comprehensive biologic properties compared to other platforms. Conclusions: GMPCs have great potential in the treatment of age-related osteoporosis via the effective delivery of Mg²⁺. Full article

Bone metastasis remains a major cause of morbidity in advanced cancer, driven not only by tumor–bone crosstalk but also by profound immune remodeling within the marrow. Myeloid-derived suppressor cells (MDSCs), including polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subsets, are increasingly recognized as central effectors of this process, integrating inflammatory signals with metabolic and stromal cues to enforce immune suppression and support skeletal colonization. In this review, we synthesize current evidence that bone metastases transform the bone marrow into an “MDSC amplifier,” where vascular and endosteal niches, CXCL12-rich stromal compartments, hypoxia, and adipocyte-derived lipids collectively promote MDSC recruitment, persistence, and functional maturation. We discuss the dominant suppressive programs deployed by MDSCs in bone (e.g., arginase-1 activity, reactive oxygen/nitrogen species, and checkpoint ligand expression), and how these mechanisms converge to impair cytotoxic T-cell and NK-cell responses while fostering regulatory T-cell dominance. Importantly, because the marrow is a hematopoietic organ, bone lesions can also generate systemic consequences through myeloid spillover, providing a mechanistic basis for reduced responsiveness to immune checkpoint blockade in bone-dominant disease. We then evaluate pharmacologic strategies to target MDSCs in the context of bone metastasis, including approaches that block trafficking (e.g., CCR2/CXCR2 axes), deplete or reprogram suppressive myeloid states (e.g., STAT3-directed strategies, differentiation therapy), and disrupt bone-resorptive feedback loops (e.g., receptor activator of NF-κB ligand (RANKL) inhibition and bisphosphonates), emphasizing rational combinations and sequencing to limit marrow toxicity. Finally, we highlight emerging single-cell and spatial profiling tools that can resolve bone-specific heterogeneity in MDSCs and guide biomarker-driven, mechanism-informed therapeutic development. Full article

The most common complication of active brucellosis in humans is osteoarticular injury. In the bone marrow microenvironment, mesenchymal stem cells (MSCs) can differentiate into either adipocytes or osteoblasts, and this balance is tightly regulated because an increase in adipogenesis may negatively affect bone formation and favor bone loss. The differentiation of MSCs into adipocytes or osteoblasts is tightly regulated by mechanisms that promote cell fate toward one lineage while repressing the other. Our study demonstrated that Brucella abortus infects MSCs but does not affect the deposition of organic and mineral matrix during osteoblast differentiation. However, the infection upregulates Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) expression in osteoblasts, which may contribute to osteoclast activation and bone resorption. Conversely, B. abortus infection significantly influences adipocyte differentiation by modulating lipolysis, lipogenesis, and interactions between lipid droplets and mitochondria. This leads to increased cellular cholesterol levels and reduced intracellular triglycerides, accompanied by glycerol release. These changes result in more differentiated adipocytes and larger lipid droplets. Consequently, we observed increased IL-6 secretion and a higher leptin/adiponectin ratio. Importantly, these effects were independent of a functional type IV secretion system (T4SS), as purified Brucella DNA fully reproduced the adipogenic phenotype. Moreover, inhibition of TLR9—the primary sensor of bacterial DNA—significantly reduced the DNA-induced adipogenic response, demonstrating that adipocyte modulation is at least in part mediated through TLR9 signaling. In summary, B. abortus promotes MSC differentiation toward an inflammatory adipocyte phenotype. It involves a TLR-9-mediated DNA detection. It may contribute to osteoarticular injury and infection-associated bone resorption. Full article

Background: Gout is an inflammatory arthritis associated with increased bone anabolism and a higher risk of ectopic bone formation. Colchicine, used to prevent and treat acute gouty flares, inhibits microtubule polymerization and has been described to promote osteoblastogenesis. In bone disorders such as osteoporosis, disruption of the osteoblast–adipocyte balance contributes to pathology, yet no therapies directly target bone marrow adiposity. Thus, we decided to investigate the impact of colchicine on the osteoblast-adipocyte balance. Methods: C3H10T1/2 mesenchymal stem cells were differentiated to both cell fates in the presence or absence of colchicine. Differentiation was assessed by studying differentiation phenotypes as well as adipocytic and osteoblastic marker genes. Disrupting microtubule homeostasis through stathmin (STMN1) silencing was employed to mimic colchicine effects on differentiation. Proteomic analysis was performed to gain further insight into colchicine’s effects on adipogenesis. Results: Colchicine promoted transcriptional changes consistent with osteoblastogenic commitment and inhibited adipogenesis, as evidenced by reduced intracellular lipid accumulation and downregulation of adipogenic marker genes. These effects were observed following both continuous and transient exposure (median fold change across adipogenic markers 0.41 and 0.59, respectively). Consistent with colchicine-induced microtubule destabilisation, microtubule disruption by STMN1 silencing also suppressed adipogenic differentiation (median fold change = 0.66), suggesting that colchicine’s anti-adipogenic effect may be due to its impact on the cytoskeleton. Conclusions: These findings indicate that colchicine can suppress adipogenic differentiation while favouring osteoblast commitment in mesenchymal stem cells. Although further validation in relevant preclinical models is required, its efficacy following transient exposure supports the exploration of site-specific strategies that limit systemic toxicity. Full article

Bone Morphogenetic Protein-2 (BMP2) is a growth factor that maintains bone homeostasis through the BMP receptor type Ia (BMPRIa) and type II (BMPRII). BMP2 promotes osteogenesis by inducing the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts; however, it can also trigger BMSC differentiation into adipocytes. BMP2’s osteo-inductive ability has made it a potential treatment for osteoporosis, yet its dual role in BMSC differentiation complicates its efficacy. High BMP2 levels cause BMPRIa cleavage, but the downstream effects and the mechanisms governing BMP2-induced osteogenesis or adipogenesis are unresolved. Here, we identify Caspase-1 as a key mediator of BMPRIa cleavage and its downstream effects on adipogenesis. We used primary BMSCs from C57BL/6 mice, stimulated with varying BMP2 concentrations, to explore BMP2-induced BMPRIa cleavage and its impact on PPARγ—a key regulator of adipogenesis. Western blotting and immunostaining using antibodies against BMPRIa and PPARγ uncovered BMPRIa cleavage and revealed the nuclear translocation of the cleaved segment, colocalizing with PPARγ. Caspase-1 inhibition significantly reduced BMPRIa cleavage and PPARγ expression, highlighting its pivotal role in adipogenic differentiation. Understanding the molecular mechanisms of BMP2-induced adipogenesis and Caspase-1 inhibition could improve BMP2 therapeutic efficacy for osteoporosis by promoting osteogenesis over adipogenesis. Full article

Bone metastases remain a leading cause of morbidity and mortality in patients with advanced breast, prostate, and lung cancers. A striking clinical feature of bone metastasis is the ability of disseminated tumor cells (DTCs) to persist in a dormant state for years or even decades before reawakening to drive overt disease. While the molecular and microenvironmental cues that induce and maintain dormancy have been increasingly studied, the mechanisms governing dormancy escape remain poorly defined yet are critical for preventing relapse. In this review, we synthesize emerging evidence on how the bone microenvironment orchestrates the transition of dormant tumor cells into proliferative lesions. We discuss how osteoclast-mediated bone resorption liberates growth factors such as TGF-β and IGF-1, fueling reactivation; how loss of osteoblast-mediated quiescence signals disrupts the endosteal niche; and how bone marrow adipocytes provide metabolic support through lipid transfer and adipokine secretion. We highlight the role of immune surveillance in maintaining dormancy and how immunosuppressive myeloid populations, regulatory T cells, and inflammatory triggers, such as neutrophil extracellular traps, promote escape. Additional emphasis is placed on extracellular matrix remodeling, mechanotransduction, angiogenic switching, and systemic factors, including aging, hormonal changes, and sympathetic nervous system activation. We also review epigenetic and metabolic reprogramming events within dormant cells that enable reactivation. Finally, we evaluate therapeutic strategies to sustain dormancy or prevent reawakening, including osteoclast-targeted therapies, immune-modulating approaches, and epigenetic or metabolic interventions. By integrating these insights, we identify key knowledge gaps and propose future directions to intercept dormancy escape and delay or prevent metastatic relapse in bone. Full article

Background and Objectives: Multiple myeloma (MM) remains an incurable plasma cell malignancy with heterogeneous clinical outcomes. Although current prognostic systems integrate biochemical and cytogenetic parameters, they do not fully capture disease complexity. Adipocytes within the bone marrow microenvironment secrete adipokines that regulate inflammation, metabolism, and immune interactions and may influence disease progression. This study aimed to assess circulating adipokines and related microenvironmental mediators as potential biomarkers of disease activity and treatment response in MM. Materials and Methods: In this case–control, cross-sectional study, the serum levels of eight adipokine-related molecules—adiponectin, leptin, resistin, chemerin, adipsin, thrombospondin-1 (TSP-1), paraoxonase-1 (PON-1), and myeloperoxidase (MPO)—were measured in 40 MM patients and 38 age- and sex-matched healthy controls. Enzyme-linked immunosorbent assays (ELISA) and bead-based multiplex immunoassays were used. Associations with prognostic markers (serum β₂-microglobulin (sB2M), LDH, albumin, hemoglobin, renal function) and treatment response were analyzed using correlation and non-parametric statistical methods. Results: Compared to the controls, MM patients exhibited significantly higher circulating levels of adiponectin, resistin, chemerin, adipsin, TSP-1, and MPO, while leptin was decreased. Among clinical correlations, chemerin and PON-1 correlated positively with sB2M, TSP-1 correlated with LDH, and MPO correlated with M-protein and albumin. Resistin was lower in patients with renal impairment and an advanced disease stage. Adiponectin and TSP-1 were significantly lower in progressive disease compared to complete remission, suggesting their potential association with treatment response. Conclusions: This study demonstrates that multiple adipokines are dysregulated in MM and exhibit distinct associations with disease burden, renal function, and therapeutic response. Novel associations identified for TSP-1, PON-1, and adipsin highlight previously unrecognized microenvironmental pathways in MM biology. Adipokine profiling may complement established prognostic markers and provide new insights into the tumour microenvironment in MM. Full article

Obesity is a chronic, multifactorial metabolic disease associated with various factors such as insulin resistance, increased adipogenesis, induction of gluconeogenesis, epigenetic mechanisms, chronic inflammatory state, and oxidative stress. Anti-obesity drugs such as Semaglutide and Tirzepatide are currently used in therapies for obese patients and exert remarkable anti-obesogenic effects, determining weight loss and inhibition of insulin resistance. The impairment of the adipogenesis process and the inhibition of the differentiation of human bone marrow mesenchymal stem cells into adipocytes should also be considered to improve the therapeutic strategies for obesity. Notably, the ability of several flavonoids to inhibit adipogenesis has been described. Flavonoids are the most abundant polyphenols in the human diet and exhibit a wide range of biological properties, including antioxidant and anti-inflammatory effects. Furthermore, many flavonoids can modulate the activity of enzymes involved in epigenetic mechanisms, which play a crucial role in obesity development. The purpose of this review is the identification of those flavonoids able to exert anti-adipogenic and anti-obesity effects in both in vitro and in vivo experimental models, with the aim of combining these natural molecules, as adjuvants, with anti-obesogenic drugs to develop innovative therapeutic approaches for the treatment of obesity pathology. Full article

Bone metastases continue to be a major cause of morbidity and mortality in patients with advanced cancers, driven by the dynamic remodeling of the bone marrow niche. Traditionally viewed as passive space-fillers, bone marrow adipocytes (BMAs) are now recognized as active regulators of tumor growth, therapeutic resistance, and skeletal pathology. BMAs comprise a significant portion of the adult marrow space, particularly in aging and obesity, and facilitate metastatic colonization through various mechanisms. These include metabolic coupling, where adipocyte-derived fatty acids fuel tumor oxidative phosphorylation; the secretion of adipokines such as leptin and IL-6, which promote epithelial-to-mesenchymal transition, invasion, and immune evasion; regulation of osteoclastogenesis via RANKL expression; and the release of extracellular vesicles that reprogram cancer cell metabolism. Clinical and experimental studies show that BMA expansion correlates with increased tumor burden and poorer outcomes in breast, prostate, lung cancers, and multiple myeloma. Additionally, BMAs actively promote therapeutic resistance through metabolic rewiring and drug sequestration. Experimental models, ranging from in vitro co-cultures to in vivo patient-derived xenografts, demonstrate the complex roles of BMAs and also reveal important translational gaps. Despite promising preclinical approaches such as metabolic inhibitors, PPARγ modulation, adipokine blockade, and lifestyle changes, no therapies directly targeting BMAs have yet reached clinical practice. This review compiles current evidence on the biology of BMAs, their tumor-promoting interactions, and potential therapeutic strategies, while also highlighting unresolved questions about BMA heterogeneity, lipid flux, and immunometabolic crosstalk. By revealing how bone marrow adipocytes actively shape the metastatic niche through metabolic, endocrine, and immunological pathways, this review highlights their potential as novel biomarkers and therapeutic targets for improving the management of bone metastases. Full article

Concentrated growth factor (CGF) is an autologous blood-derived product widely used in regenerative medicine due to its high concentration of growth factors and platelets. In this study, the ability of primary stem cells isolated from human CGF to differentiate into adipocytes, endothelial cells, and neuronal-like cells was evaluated in vitro. CGF primary cells (CPCs) were obtained from CGF fragments and characterized after one month in culture. These cells were positive for the surface markers CD105, CD45, CD31, and CD14, and also expressed mRNA levels of the stemness markers Nanog and Oct3/4 comparable to human bone marrow mesenchymal stem cells (BMSCs). Results showed that, following appropriate differentiation protocols, CPCs, similarly to BMSCs, were able to differentiate into adipogenic, endothelial, and neuronal lineages, acquiring specific phenotypic and molecular markers. Adipogenic induction resulted in lipid accumulation and the upregulation of key genes, including PLIN2, FABP4, CD36, and FASN. Under pro-endothelial conditions, the cells exhibited increased expression of endothelial markers, eNOS, VEGFR-2, and CD31. Neuronal induction promoted the expression of β-tubulin III, Nestin, and Neurofilament. Overall, this work highlights the remarkable plasticity of CPCs and supports their potential application in multilineage regenerative therapies. Full article

Background/Objectives: Obesity and type 2 diabetes mellitus (T2DM) profoundly disrupt lipid metabolism within local microenvironments of skeletal muscle and its associated connective tissues, including adipose tissue, bone, and fascia. However, the role of local communication between skeletal muscle and its proximal connective tissues in propagating metabolic dysfunction is incompletely understood. This narrative review synthesizes current evidence on these local metabolic interactions, highlighting novel insights and existing gaps. Methods: We conducted a comprehensive literature analysis of primary research published in the last decade, sourced from PubMed, Web of Science, and ScienceDirect. Studies were selected for relevance to skeletal muscle, adipose tissue, fascia, and bone lipid metabolism in the context of obesity and T2DM, with emphasis on molecular, cellular, and paracrine mechanisms of local crosstalk. Findings were organized into thematic sections addressing physiological regulation, pathological remodeling, and inter-organ signaling pathways. Results: Our synthesis reveals that local lipid dysregulation in obesity and T2DM involves altered fatty acid transporter dynamics, mitochondrial overload, fibro-adipogenic remodeling, and compartment-specific adipose tissue dysfunction. Crosstalk via myokines, adipokines, osteokines, bioactive lipids, and exosomal miRNAs integrates metabolic responses across these tissues, amplifying insulin resistance and lipotoxic stress. Emerging evidence highlights the underappreciated roles of fascia and marrow adipocytes in regional lipid handling. Conclusions: Collectively, these insights underscore the pivotal role of inter-tissue crosstalk among skeletal muscle, adipose tissue, bone, and fascia in orchestrating lipid-induced insulin resistance, and highlight the need for integrative strategies that target this multicompartmental network to mitigate metabolic dysfunction in obesity and T2DM. Full article

Xylosyltransferase-I (XT-I) plays a crucial role in skeletal development and cartilage integrity. An XT-I deficiency is linked to severe bone disorders, such as Desbuquois dysplasia type 2. While animal models have provided insights into XT-I’s role during skeletal development, its specific effects on adult bone homeostasis, particularly in human mesenchymal stem cell (hMSC) differentiation, remain unclear. This study investigates how XT-I deficiency impacts the differentiation of hMSCs into chondrocytes, osteoblasts, and adipocytes—key processes in bone formation and repair. The aim of this study was to elucidate for the first time the molecular mechanisms by which XT-I deficiency leads to impaired bone homeostasis. Using CRISPR-Cas9-mediated gene editing, we generated XYLT1 knockdown (KD) hMSCs to assess their differentiation potential. Our findings revealed significant disruption in the chondrogenic differentiation in KD hMSCs, characterized by the altered expression of regulatory factors and extracellular matrix components, suggesting premature chondrocyte hypertrophy. Despite the presence of perilipin-coated lipid droplets in the adipogenic pathway, the overall leptin mRNA and protein expression was reduced in KD hMSCs, indicating a compromised lipid metabolism. Conversely, osteogenic differentiation was largely unaffected, with KD and wild-type hMSCs exhibiting comparable mineralization processes, indicating that critical aspects of osteogenesis were preserved despite the XYLT1 deficiency. In summary, these results underscore XT-I’s pivotal role in regulating differentiation pathways within the bone marrow niche, influencing cellular functions critical for skeletal health. A deeper insight into bone biology may pave the way for the development of innovative therapeutic approaches to improve bone health and treat skeletal disorders. Full article

In patients diagnosed with multiple myeloma (MM), the primary complaints at the time of diagnosis are often related to bone involvement, significantly impacting quality of life and increasing both morbidity and mortality. Obesity is associated with a chronic inflammatory state that results in the production of various cytokines and adipokines, which may promote bone destruction. Adiponectin, an adipokine predominantly secreted by adipocytes, is notably diminished in circulation among individuals with obesity, a phenomenon that has also been observed in MM. This reduction may contribute to the disruption of an already compromised bone architecture. The increase in adipose tissue is associated with heightened leptin production, a key adipokine, which can play a significant role in the pathophysiology of MM and its related bone complications. Obesity is associated with hyperinsulinemia and increased levels of free IGF-1. In MM, IGF-1 plays a critical role as a growth factor, produced by both myeloma cells and osteoclasts within the bone marrow microenvironment. Our gathered data indicates a significant relationship between the adipokines produced by adipose tissue and the bone matrix, particularly in the context of obesity and MM. However, it is important to note that the existing body of research on this topic is relatively sparse, with the majority of studies conducted on murine models rather than human subjects. This limitation highlights a critical need for further investigation to elucidate the precise mechanisms that contribute to bone destruction under these conditions. Full article