ABSTRACT
Beta-tricalcium phosphate (ß-TCP) scaffolds manufactured through the foam replication method are widely employed in bone tissue regeneration. The mechanical strength of these scaffolds is a significant challenge, partly due to the rheological properties of the original suspension. Various strategies have been explored to enhance the mechanical properties. In this research, ß-TCP scaffolds containing varying concentrations (0.25-1.00 wt%) of multi-walled carbon nanotubes (MWCNT) were developed. The findings indicate that the addition of MWCNTs led to a concentration-dependent improvement in the viscosity of ß-TCP suspensions. All the prepared slurries exhibited viscoelastic behavior, with the storage modulus surpassing the loss modulus. The three time interval tests revealed that MWCNT-incorporated ß-TCP suspensions exhibited faster structural recovery compared to pure ß-TCP slurries. Introducing MWCNT modified compressive strength, and the optimal improvement was obtained using 0.75 wt% MWCNT. The in vitro degradation of ß-TCP was also reduced by incorporating MWCNT. While the inclusion of carbon nanotubes had a marginal negative impact on the viability and attachment of MC3T3-E1 cells, the number of viable cells remained above 70% of the control group. Additionally, the results demonstrated that the scaffold increased the expression level of osteocalcin, osteoponthin, and alkaline phosphatase genes of adiposed-derived stem cells; however, higher levels of gene expersion were obtained by using MWCNT. The suitability of MWCNT-modified ß-TCP suspensions for the foam replication method can be assessed by evaluating their rheological behavior, aiding in determining the critical additive concentration necessary for a successful coating process.
Subject(s)
Calcium Phosphates , Nanotubes, Carbon , Tissue Engineering , Tissue Scaffolds , Calcium Phosphates/chemistry , Nanotubes, Carbon/chemistry , Tissue Scaffolds/chemistry , Tissue Engineering/methods , Animals , Mice , Cell Line , Bone and Bones/metabolism , Cell Survival/drug effects , Materials Testing , Bone Regeneration/drug effects , Osteoblasts/metabolism , Osteoblasts/drug effects , Osteoblasts/cytology , ViscosityABSTRACT
Ageing is the most prominent risk for osteoarthritis (OA) development. This study aimed to investigate the role of phosphoinositide-specific phospholipase Cγ (PLCγ) 1, previously linked to OA progression, in regulating age-related changes in articular cartilage and subchondral bone. d-galactose (d-Gal) was employed to treat chondrocytes from rats and mice or injected intraperitoneally into C57BL/6 mice. RTCA, qPCR, Western blot and immunohistochemistry assays were used to evaluate cell proliferation, matrix synthesis, senescence genes and senescence-associated secretory phenotype, along with PLCγ1 expression. Subchondral bone morphology was assessed through micro-CT. In mice with chondrocyte-specific Plcg1 deficiency (Plcg1flox/flox; Col2a1-CreERT), articular cartilage and subchondral bone were examined over different survival periods. Our results showed that d-Gal induced chondrocyte senescence, expedited articular cartilage ageing and caused subchondral bone abnormalities. In d-Gal-induced chondrocytes, diminished PLCγ1 expression was observed, and its further inhibition by U73122 exacerbated chondrocyte senescence. Plcg1flox/flox; Col2a1-CreERT mice exhibited more pronounced age-related changes in articular cartilage and subchondral bone compared to Plcg1flox/flox mice. Therefore, not only does d-Gal induce senescence in chondrocytes and age-related changes in articular cartilage and subchondral bone, as well as diminished PLCγ1 expression, but PLCγ1 deficiency in chondrocytes may also accelerate age-related changes in articular cartilage and subchondral bone. PLCγ1 may be a promising therapeutic target for mitigating age-related changes in joint tissue.
Subject(s)
Cartilage, Articular , Chondrocytes , Mice, Inbred C57BL , Phospholipase C gamma , Animals , Chondrocytes/metabolism , Phospholipase C gamma/metabolism , Phospholipase C gamma/genetics , Cartilage, Articular/metabolism , Cartilage, Articular/pathology , Mice , Aging/metabolism , Osteoarthritis/pathology , Osteoarthritis/metabolism , Osteoarthritis/genetics , Osteoarthritis/etiology , Cellular Senescence , Rats , Estrenes/pharmacology , Galactose/metabolism , Cell Proliferation , Male , Bone and Bones/metabolism , Bone and Bones/pathology , Bone and Bones/diagnostic imaging , Pyrrolidinones/pharmacologyABSTRACT
Bone is a dynamic tissue that can always regenerate itself through remodeling to maintain biofunctionality. This tissue performs several vital physiological functions. However, bone scaffolds are required for critical-size damages and fractures, and these can be addressed by bone tissue engineering. Bone tissue engineering (BTE) has the potential to develop scaffolds for repairing critical-size damaged bone. BTE is a multidisciplinary engineered scaffold with the desired properties for repairing damaged bone tissue. Herein, we have provided an overview of the common carbohydrate polymers, fundamental structural, physicochemical, and biological properties, and fabrication techniques for bone tissue engineering. We also discussed advanced biofabrication strategies and provided the limitations and prospects by highlighting significant issues in bone tissue engineering. There are several review articles available on bone tissue engineering. However, we have provided a state-of-the-art review article that discussed recent progress and trends within the last 3-5 years by emphasizing challenges and future perspectives.
Subject(s)
Biocompatible Materials , Bone and Bones , Carbohydrates , Ceramics , Tissue Engineering , Tissue Scaffolds , Tissue Engineering/methods , Ceramics/chemistry , Humans , Bone and Bones/metabolism , Tissue Scaffolds/chemistry , Animals , Carbohydrates/chemistry , Biocompatible Materials/chemistry , Bone Regeneration , Bone Substitutes/chemistry , Polymers/chemistryABSTRACT
The design of three-dimensional (3D) scaffolds should focus on creating highly porous, 3D structures with an interconnected pore network that supports cell growth. The scaffold's pore interconnectivity is directly linked to vascularization, cell seeding, guided cell migration, and transportation of nutrients and metabolic waste. In this study, different types of food flavors including monosodium glutamate, sugar, and sodium chloride were used as the porogens along with PCL/PVP blend polymer for solvent casting/particulate leaching method. The morphology, porosity, interconnectivity, chemical composition, water absorption, and mechanical properties of the fabricated scaffolds are carefully characterized. The scaffolds are biocompatible in bothin vitroandin vivoexperiments and do not trigger any inflammatory response while enhancing new bone formation and vascularization in rabbit calvaria critical-sized defects. The new bone merges and becomes denser along with the experiment timeline. The results indicate that the 3D PCL/PVP scaffolds, using monosodium glutamate as porogen, exhibited suitable biological performance and held promise for bone tissue engineering in oral and maxillofacial surgery.
Subject(s)
Biocompatible Materials , Sodium Glutamate , Solvents , Tissue Engineering , Tissue Scaffolds , Animals , Tissue Scaffolds/chemistry , Rabbits , Tissue Engineering/methods , Porosity , Solvents/chemistry , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Polyesters/chemistry , Materials Testing , Skull/drug effects , Polyvinyls/chemistry , Bone Regeneration/drug effects , Osteogenesis/drug effects , Bone Substitutes/chemistry , Bone Substitutes/pharmacology , Bone and Bones/metabolismABSTRACT
Despite their diverse physiologies and roles, the heart, skeletal muscles, and smooth muscles all derive from a common embryonic source as bones. Moreover, bone tissue, skeletal and smooth muscles, and the heart share conserved signaling pathways. The maintenance of skeletal health is precisely regulated by osteocytes, osteoblasts, and osteoclasts through coordinated secretion of bone-derived factors known as osteokines. Increasing evidence suggests the involvement of osteokines in regulating atherosclerotic vascular disease. Therefore, this review aims to examine the evidence for the role of osteokines in atherosclerosis development and progression comprehensively. Specifically discussed are extensively studied osteokines in atherosclerosis such as osteocalcin, osteopontin, osteoprotegerin, and fibroblast growth factor 23. Additionally, we highlighted the effects of exercise on modulating these key regulators derived from bone tissue metabolism. We believe that gaining an enhanced understanding of how osteocalcin contributes to the process of atherosclerosis will enable us to develop targeted and comprehensive therapeutic strategies against diseases associated with its progression.
Subject(s)
Atherosclerosis , Osteocalcin , Humans , Atherosclerosis/metabolism , Atherosclerosis/pathology , Animals , Osteocalcin/metabolism , Osteopontin/metabolism , Fibroblast Growth Factors/metabolism , Osteoprotegerin/metabolism , Bone and Bones/metabolism , Bone and Bones/pathologyABSTRACT
Introduction: Fibroblast growth factor 20 (Fgf20), a member of the Fgf9 subfamily, was identified as an important regulator of bone differentiation and homeostasis processes. However, the role of Fgf20 in bone physiology has not been approached yet. Here we present a comprehensive bone phenotype analysis of mice with functional ablation of Fgf20. Methods: The study conducts an extensive analysis of Fgf20 knockout mice compared to controls, incorporating microCT scanning, volumetric analysis, Fgf9 subfamily expression and stimulation experiment and histological evaluation. Results: The bone phenotype could be detected especially in the area ofâ the lumbar and caudal part of the spine and in fingers. Regarding the spine, Fgf20-/- mice exhibited adhesions of the transverse process of the sixth lumbar vertebra to the pelvis as well as malformations in the distal part of their tails. Preaxial polydactyly and polysyndactyly in varying degrees of severity were also detected. High resolution microCT analysis of distal femurs and the fourth lumbar vertebra showed significant differences in structure and mineralization in both cortical and trabecular bone. These findings were histologically validated and may be associated with the expression of Fgf20 in chondrocytes and their progenitors. Moreover, histological sections demonstrated increased bone tissue formation, disruption of Fgf20-/- femur cartilage, and cellular-level alterations, particularly in osteoclasts. We also observed molar dysmorphology, including root taurodontism, and described variations in mineralization and dentin thickness. Discussion: Our analysis provides evidence that Fgf20, together with other members of the Fgf9 subfamily, plays a crucial regulatory role in skeletal development and bone homeostasis.
Subject(s)
Fibroblast Growth Factors , Mice, Knockout , Animals , Mice , Fibroblast Growth Factors/metabolism , Fibroblast Growth Factors/genetics , X-Ray Microtomography , Bone and Bones/metabolism , Bone and Bones/pathology , Bone and Bones/diagnostic imaging , Bone and Bones/abnormalities , Calcification, Physiologic , Male , Osteogenesis , Female , Mice, Inbred C57BL , PhenotypeABSTRACT
Degenerative disorders like osteoarthritis (OA) might impair the ability of tissue-resident mesenchymal stem/stromal cells (MSCs) for tissue regeneration. As primary cells with MSC-like properties are exploited for patient-derived stem cell therapies, a detailed evaluation of their in vitro properties is needed. Here, we aimed to compare synovium-derived and bone-derived MSCs in early hip OA with those of patients without OA (non-OA). Tissues from three synovial sites of the hip (paralabral synovium, cotyloid fossa, inner surface of peripheral capsule) were collected along with peripheral trabecular bone from 16 patients undergoing hip arthroscopy (8 early OA and 8 non-OA patients). Primary cells isolated from tissues were compared using detailed in vitro analyses. Gene expression profiling was performed for the skeletal stem cell markers podoplanin (PDPN), CD73, CD164 and CD146 as well as for immune-related molecules to assess their immunomodulatory potential. Synovium-derived and bone-derived MSCs from early OA patients showed comparable clonogenicity, cumulative population doublings, osteogenic, adipogenic and chondrogenic potential, and immunophenotype to those of non-OA patients. High PDPN/low CD146 profile (reminiscent of skeletal stem cells) was identified mainly for non-OA MSCs, while low PDPN/high CD146 mainly defined early OA MSCs. These data suggest that MSCs from early OA patients are not affected by degenerative changes in the hip. Moreover, the synovium represents an alternative source of MSCs for patient-derived stem cell therapies, which is comparable to bone. The expression profile reminiscent of skeletal stem cells suggests the combination of low PDPN and high CD146 as potential biomarkers in early OA.
Subject(s)
Mesenchymal Stem Cells , Synovial Membrane , Humans , Mesenchymal Stem Cells/metabolism , Synovial Membrane/pathology , Synovial Membrane/metabolism , Female , Male , Middle Aged , Cell Differentiation , Aged , Osteoarthritis/pathology , Osteoarthritis/metabolism , Bone and Bones/pathology , Bone and Bones/metabolism , Adult , Biomarkers/metabolism , Chondrogenesis , Osteogenesis , Cells, CulturedABSTRACT
The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.
Subject(s)
Adipose Tissue, White , Bone and Bones , Diet, High-Fat , Intercellular Signaling Peptides and Proteins , Mice, Knockout , Obesity , Osteoblasts , Animals , Obesity/metabolism , Obesity/genetics , Obesity/etiology , Adipose Tissue, White/metabolism , Osteoblasts/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Intercellular Signaling Peptides and Proteins/genetics , Mice , Diet, High-Fat/adverse effects , Bone and Bones/metabolism , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Male , Adipose Tissue, Brown/metabolism , Mice, Inbred C57BL , Adipocytes/metabolism , Signal TransductionABSTRACT
The high incidence of bone defect-related diseases caused by trauma, infection, and tumor resection has greatly stimulated research in the field of bone regeneration. Generally, bone healing is a long and complicated process wherein manipulating the biological activity of interventional scaffolds to support long-term bone regeneration is significant for treating bone-related diseases. It has been reported that some physical cues can act as growth factor substitutes to promote osteogenesis through continuous activation of endogenous signaling pathways. This review focuses on the latest progress in bone repair by remote actuation and on-demand activation of biomaterials pre-incorporated with physical cues (heat, electricity, and magnetism). As an alternative method to treat bone defects, physical cues show many advantages, including effectiveness, noninvasiveness, and remote manipulation. First, we introduce the impact of different physical cues on bone repair and potential internal regulatory mechanisms. Subsequently, biomaterials that mediate various physical cues in bone repair and their respective characteristics are summarized. Additionally, challenges are discussed, aiming to provide new insights and suggestions for developing intelligent biomaterials to treat bone defects and promote clinical translation.
Subject(s)
Biocompatible Materials , Bone Regeneration , Tissue Scaffolds , Bone Regeneration/drug effects , Biocompatible Materials/chemistry , Humans , Animals , Tissue Scaffolds/chemistry , Osteogenesis/drug effects , Tissue Engineering/methods , Bone and Bones/metabolismABSTRACT
Bone development is characterized by complex regulation mechanisms, including signal transduction and transcription factor-related pathways, glycobiological processes, cellular interactions, transportation mechanisms, and, importantly, chemical formation resulting from hydroxyapatite. Any abnormal regulation in the bone development processes causes skeletal system-related problems. To some extent, the avascularity of cartilage and bone makes drug delivery more challenging than that of soft tissues. Recent studies have implemented many novel bone-targeting approaches to overcome drawbacks. However, none of these strategies fully corrects skeletal dysfunction, particularly in growth plate-related ones. Although direct recombinant enzymes (e.g., Vimizim for Morquio, Cerezyme for Gaucher, Elaprase for Hunter, Mepsevii for Sly diseases) or hormone infusions (estrogen for osteoporosis and osteoarthritis), traditional gene delivery (e.g., direct infusion of viral or non-viral vectors with no modifications on capsid, envelope, or nanoparticles), and cell therapy strategies (healthy bone marrow or hematopoietic stem cell transplantation) partially improve bone lesions, novel delivery methods must be addressed regarding target specificity, less immunogenicity, and duration in circulation. In addition to improvements in bone delivery, potential regulation of bone development mechanisms involving receptor-regulated pathways has also been utilized. Targeted drug delivery using organic and inorganic compounds is a promising approach in mostly preclinical settings and future clinical translation. This review comprehensively summarizes the current bone-targeting strategies based on bone structure and remodeling concepts while emphasizing potential approaches for future bone-targeting systems.
Subject(s)
Drug Delivery Systems , Humans , Animals , Drug Delivery Systems/methods , Bone and Bones/metabolism , Bone Diseases/therapy , Bone Development/drug effects , Genetic Therapy/methodsABSTRACT
Rhodiola rosea, a long-lived herbaceous plant from the Crassulaceae group, contains the active compound salidroside, recognized as an adaptogen with significant therapeutic potential for bone metabolism. Salidroside promotes osteoblast proliferation and differentiation by activating critical signaling pathways, including bone morphogenetic protein-2 and adenosine monophosphate-activated protein kinase, essential for bone formation and growth. It enhances osteogenic activity by increasing alkaline phosphatase activity and mineralization markers, while upregulating key regulatory proteins including runt-related transcription factor 2 and osterix. Additionally, salidroside facilitates angiogenesis via the hypoxia-inducible factor 1-alpha and vascular endothelial growth factor pathway, crucial for coupling bone development with vascular support. Its antioxidant properties offer protection against bone loss by reducing oxidative stress and promoting osteogenic differentiation through the nuclear factor erythroid 2-related factor 2 pathway. Salidroside has the capability to counteract the negative effects of glucocorticoids on bone cells and prevents steroid-induced osteonecrosis. Additionally, it exhibits multifaceted anti-inflammatory actions, notably through the inhibition of tumor necrosis factor-alpha and interleukin-6 expression, while enhancing the expression of interleukin-10. This publication presents a comprehensive review of the literature on the impact of salidroside on various aspects of bone tissue metabolism, emphasizing its potential role in the prevention and treatment of osteoporosis and other diseases affecting bone physiology.
Subject(s)
Bone and Bones , Glucosides , Osteoblasts , Osteogenesis , Osteoporosis , Phenols , Glucosides/pharmacology , Humans , Phenols/pharmacology , Bone and Bones/drug effects , Bone and Bones/metabolism , Osteogenesis/drug effects , Osteoporosis/drug therapy , Animals , Osteoblasts/drug effects , Osteoblasts/metabolism , Rhodiola/chemistry , Signal Transduction/drug effects , Antioxidants/pharmacology , Cell Differentiation/drug effects , Anti-Inflammatory Agents/pharmacologyABSTRACT
Immunodeficiency can disrupt normal physiological activity and function. In this study, donkey bone collagen peptide (DP) and its iron chelate (DPI) were evaluated their potential as immunomodulators in cyclophosphamide (Cytoxan®, CTX)-induced Balb/c mice. The femoral tissue, lymphocytes, and serum from groups of mice were subjected to hematoxylin and eosin (H&E) staining, methylthiazolyldiphenyl-tetrazolium bromide (MTT) cell proliferation assays, and enzyme-linked immunosorbent assay (ELISA), respectively. Furthermore, a non-targeted metabolomics analysis based on UPLC-MS/MS and a reverse transcription polymerase chain reaction (RT-qPCR) technology were used to explore the specific metabolic pathways of DPI regulating immunocompromise. The results showed that CTX was able to significantly reduce the proliferative activity of mouse splenic lymphocytes and led to abnormal cytokine expression. After DP and DPI interventions, bone marrow tissue damage was significantly improved. In particular, DPI showed the ability to regulate the levels of immune factors more effectively than Fe2+ and DP. Furthermore, metabolomic analysis in both positive and negative ion modes showed that DPI and DP jointly regulated the levels of 20 plasma differential metabolites, while DPI and Fe2+ jointly regulated 14, and all 3 jointly regulated 10. Fe2+ and DP regulated energy metabolism and pyrimidine metabolism pathways, respectively. In contrast, DPI mainly modulated the purine salvage pathway and the JAK/STAT signaling pathway, which are the key to immune function. Therefore, DPI shows more effective immune regulation than Fe2+ and DP alone, and has good application potential in improving immunosuppression.
Subject(s)
Collagen , Cyclophosphamide , Equidae , Iron Chelating Agents , Mice, Inbred BALB C , Animals , Collagen/metabolism , Iron Chelating Agents/pharmacology , Mice , Cell Proliferation/drug effects , Peptides/pharmacology , Lymphocytes/drug effects , Lymphocytes/metabolism , Immunosuppressive Agents/pharmacology , Metabolomics , Cytokines/metabolism , Male , Bone and Bones/drug effects , Bone and Bones/metabolism , Immunosuppression TherapyABSTRACT
The aim of the present review is to discuss the roles of vitamin K (phylloquinone or menaquinones) and vitamin K-dependent proteins, and the combined action of the vitamins K and D, for the maintenance of bone health. The most relevant vitamin K-dependent proteins in this respect are osteocalcin and matrix Gla-protein (MGP). When carboxylated, these proteins appear to have the ability to chelate and import calcium from the blood to the bone, thereby reducing the risk of osteoporosis. Carboxylated osteocalcin appears to contribute directly to bone quality and strength. An adequate vitamin K status is required for the carboxylation of MGP and osteocalcin. In addition, vitamin K acts on bone metabolism by other mechanisms, such as menaquinone 4 acting as a ligand for the nuclear steroid and xenobiotic receptor (SXR). In this narrative review, we examine the evidence for increased bone mineralization through the dietary adequacy of vitamin K. Summarizing the evidence for a synergistic effect of vitamin K and vitamin D3, we find that an adequate supply of vitamin K, on top of an optimal vitamin D status, seems to add to the benefit of maintaining bone health. More research related to synergism and the possible mechanisms of vitamins D3 and K interaction in bone health is needed.
Subject(s)
Bone and Bones , Osteocalcin , Vitamin D , Vitamin K , Humans , Vitamin K/pharmacology , Bone and Bones/metabolism , Bone and Bones/drug effects , Osteocalcin/metabolism , Vitamin D/metabolism , Calcium/metabolism , Matrix Gla Protein , Osteoporosis/prevention & control , Extracellular Matrix Proteins/metabolism , Calcium-Binding Proteins/metabolism , Nutritional Status , Dietary SupplementsABSTRACT
Osteoporosis in menopausal women requires alternatives to current medications, considering their adverse effects. In this context, probiotics and isoflavone products are promising dietary interventions. The objective of our study was to examine the impacts of Lactobacillus acidophilus and its combination with daidzein and tempeh on calcium status, calcium transporters, and bone metabolism biomarkers in a post-menopausal osteoporotic rat model. A total of 48 female Wistar rats were exposed to a two-stage experiment involving calcium deficit induction and subsequent dietary interventions across six groups. Calcium levels, the gene expression of TRPV5 and TRPV6 calcium transporters, bone histopathology, serum bone metabolism markers, and blood biochemistry were evaluated. The results revealed that, while decreasing serum calcium levels, the groups that received the probiotic L. acidophilus and isoflavone combination exhibited increased bone metabolism biomarkers and decreased calcium transporter expressions, akin to the effects of bisphosphonate. Additionally, significant improvements in bone histopathology were observed in these groups. However, the group receiving probiotic L. acidophilus alone did not exhibit significant changes in bone resorption biomarkers, calcium transporter expression, or various blood parameters. Meanwhile, the combination of probiotic L. acidophilus with tempeh positively influenced hematological parameters and reduced cholesterol and triglyceride levels, but it led to elevated blood glucose levels. Correlation analyses highlighted associations between serum calcium levels, calcium transporter expression, and bone metabolism biomarkers. In conclusion, our findings suggest that the daily consumption of probiotic L. acidophilus in combination with isoflavone products may improve bone health in ovariectomized rats, warranting further research to elucidate potential interactions with other nutrients.
Subject(s)
Biomarkers , Bone and Bones , Calcium , Disease Models, Animal , Isoflavones , Lactobacillus acidophilus , Probiotics , Rats, Wistar , Animals , Female , Isoflavones/pharmacology , Probiotics/pharmacology , Calcium/blood , Biomarkers/blood , Rats , Bone and Bones/metabolism , Bone and Bones/drug effects , TRPV Cation Channels/metabolism , Osteoporosis, Postmenopausal , PostmenopauseABSTRACT
Extracellular vesicles (EVs) are membrane-enclosed bio-nanoparticles secreted by cells and naturally evolved to transport various bioactive molecules between cells and even organisms. These cellular objects are considered one of the most promising bio-nanovehicles for the delivery of native and exogenous molecular cargo. However, many challenges with state-of-the-art EV-based candidates as drug carriers still exist, including issues with scalability, batch-to-batch reproducibility, and cost-sustainability of the final therapeutic formulation. Microalgal extracellular vesicles, which we named nanoalgosomes, are naturally released by various microalgal species. Here, we evaluate the innate biological properties of nanoalgosomes derived from cultures of the marine microalgae Tetraselmis chuii, using an optimized manufacturing protocol. Our investigation of nanoalgosome biocompatibility in preclinical models includes toxicological analyses, using the invertebrate model organism Caenorhabditis elegans, hematological and immunological evaluations ex vivo and in mice. We evaluate nanoalgosome cellular uptake mechanisms in C. elegans at cellular and subcellular levels, and study their biodistribution in mice with accurate space-time resolution. Further examination highlights the antioxidant and anti-inflammatory bioactivities of nanoalgosomes. This holistic approach to nanoalgosome functional characterization demonstrates that they are biocompatible and innate bioactive effectors with unique bone tropism. These findings suggest that nanoalgosomes have significant potential for future therapeutic applications.
Subject(s)
Anti-Inflammatory Agents , Antioxidants , Extracellular Vesicles , Microalgae , Extracellular Vesicles/metabolism , Animals , Microalgae/metabolism , Mice , Anti-Inflammatory Agents/pharmacology , Antioxidants/metabolism , Antioxidants/pharmacology , Caenorhabditis elegans/metabolism , Biocompatible Materials/chemistry , Chlorophyta/metabolism , Bone and Bones/metabolism , TropismABSTRACT
Glucocorticoids (GC) and parathyroid hormone (PTH) are widely used therapeutic endocrine hormones where their effects on bone and joint arise from actions on multiple skeletal cell types. In osteocytes, GC and PTH exert opposing effects on perilacunar canalicular remodeling (PLR). Suppressed PLR can impair bone quality and joint homeostasis, including in GC-induced osteonecrosis. However, combined effects of GC and PTH on PLR are unknown. Given the untapped potential to target osteocytes to improve skeletal health, this study sought to test the feasibility of therapeutically mitigating PLR suppression. Focusing on subchondral bone and joint homeostasis, we hypothesize that PTH(1-34), a PLR agonist, could rescue GC-suppressed PLR. The skeletal effects of GC and PTH(1-34), alone or combined, were examined in male and female mice by micro-computed tomography, mechanical testing, histology, and gene expression analysis. For each outcome, females were more responsive to GC and PTH(1-34) than males. GC and PTH(1-34) exerted regional differences, with GC increasing trabecular bone volume but reducing cortical bone thickness, stiffness, and ultimate force. Despite PTH(1-34)'s anabolic effects on trabecular bone, it did not rescue GC's catabolic effects on cortical bone. Likewise, cartilage integrity and subchondral bone apoptosis, tartrate-resistant acid phosphatase (TRAP) activity, and osteocyte lacunocanalicular networks showed no evidence that PTH(1-34) could offset GC-dependent effects. Rather, GC and PTH(1-34) each increased cortical bone gene expression implicated in bone resorption by osteoclasts and osteocytes, including Acp5, Mmp13, Atp6v0d2, Ctsk, differences maintained when GC and PTH(1-34) were combined. Since PTH(1-34) is insufficient to rescue GC's effects on young female mouse bone, future studies are needed to determine if osteocyte PLR suppression, due to GC, aging, or other factors, can be offset by a PLR agonist.
Subject(s)
Bone Density , Bone Remodeling , Glucocorticoids , Osteocytes , Parathyroid Hormone , Animals , Osteocytes/drug effects , Osteocytes/metabolism , Parathyroid Hormone/pharmacology , Female , Male , Mice , Glucocorticoids/pharmacology , Bone Remodeling/drug effects , Bone Density/drug effects , Mice, Inbred C57BL , Bone and Bones/drug effects , Bone and Bones/metabolism , X-Ray MicrotomographyABSTRACT
Bone marrow adipocytes (BMAds) affect bone homeostasis, but the mechanism remains unclear. Here, we showed that exercise inhibited PCNA clamp-associated factor (PCLAF) secretion from the bone marrow macrophages to inhibit BMAds senescence and thus alleviated skeletal aging. The genetic deletion of PCLAF in macrophages inhibited BMAds senescence and delayed skeletal aging. In contrast, the transplantation of PCLAF-mediated senescent BMAds into the bone marrow of healthy mice suppressed bone turnover. Mechanistically, PCLAF bound to the ADGRL2 receptor to inhibit AKT/mTOR signaling that triggered BMAds senescence and subsequently spread senescence among osteogenic and osteoclastic cells. Of note, we developed a PCLAF-neutralizing antibody and showed its therapeutic effects on skeletal health in old mice. Together, these findings identify PCLAF as an inducer of BMAds senescence and provide a promising way to treat age-related osteoporosis.
Subject(s)
Adipocytes , Aging , Cellular Senescence , Animals , Adipocytes/metabolism , Cellular Senescence/physiology , Mice , Aging/physiology , Mice, Inbred C57BL , Bone Marrow Cells/metabolism , Bone and Bones/metabolism , Bone and Bones/physiology , Male , Osteogenesis/physiology , Signal Transduction , Macrophages/metabolismABSTRACT
Osteoporosis and osteoarthritis continue to pose significant challenges to the aging population, with limited preventive options and pharmacological treatments often accompanied by side effects. Amidst ongoing efforts to discover new therapeutic agents, tocotrienols (TTs) have emerged as potential candidates. Derived from annatto bean and palm oil, TTs have demonstrated efficacy in improving skeletal and joint health in numerous animal models of bone loss and osteoarthritis. Mechanistic studies suggest that TTs exert their effects through antioxidant, anti-inflammatory, Wnt-suppressive, and mevalonate-modulating mechanisms in bone, as well as through self-repair mechanisms in chondrocytes. However, human clinical trials in this field remain scarce. In conclusion, TTs hold promise as agents for preventing osteoporosis and osteoarthritis, pending further evidence from human clinical trials.
Subject(s)
Osteoarthritis , Osteoporosis , Tocotrienols , Tocotrienols/therapeutic use , Tocotrienols/pharmacology , Humans , Animals , Osteoarthritis/drug therapy , Osteoarthritis/prevention & control , Osteoporosis/drug therapy , Osteoporosis/prevention & control , Bone and Bones/drug effects , Bone and Bones/metabolismABSTRACT
The intricate interplay between the muscle and bone tissues is a fundamental aspect of musculoskeletal physiology. Over the past decades, emerging research has highlighted the pivotal role of lipid signaling in mediating communication between these tissues. This chapter delves into the multifaceted mechanisms through which lipids, particularly phospholipids, sphingolipids, and eicosanoids, participate in orchestrating cellular responses and metabolic pathways in both muscle and bone. Additionally, we examine the clinical implications of disrupted lipid signaling in musculoskeletal disorders, offering insights into potential therapeutic avenues. This chapter aims to shed light on the complex lipid-driven interactions between the muscle and bone tissues, paving the way for a deeper understanding of musculoskeletal health and disease.
Subject(s)
Lipid Metabolism , Musculoskeletal Diseases , Signal Transduction , Animals , Humans , Bone and Bones/metabolism , Eicosanoids/metabolism , Muscle, Skeletal/metabolism , Musculoskeletal Diseases/metabolism , Phospholipids/metabolism , Sphingolipids/metabolismABSTRACT
Bone is a unique type of mineralised connective tissue that can support and protect soft tissues, contain bone marrow, and allow movement [...].