Revolutionizing osteoarthritis treatment: How mesenchymal stem cells hold the key.

Osteoarthritis (OA) is a multifaceted disease characterized by imbalances in extracellular matrix metabolism, chondrocyte and synoviocyte senescence, as well as inflammatory responses mediated by macrophages. Although there have been notable advancements in pharmacological and surgical interventions, achieving complete remission of OA remains a formidable challenge, oftentimes accompanied by significant side effects. Mesenchymal stem cells (MSCs) have emerged as a promising avenue for OA treatment, given their ability to differentiate into chondrocytes and facilitate cartilage repair, thereby mitigating the impact of an inflammatory microenvironment induced by macrophages. This comprehensive review aims to provide a concise overview of the diverse roles played by MSCs in the treatment of OA, while elucidating the underlying mechanisms behind these contributions. Specifically, the roles include: (a) Promotion of chondrocyte and synoviocyte regeneration; (b) Inhibition of extracellular matrix degradation; (c) Attenuating the macrophage-induced inflammatory microenvironment; (d) Alleviation of pain. Understanding the multifaceted roles played by MSCs in OA treatment is paramount for developing novel therapeutic strategies. By harnessing the regenerative potential and immunomodulatory properties of MSCs, it may be possible to devise more effective and safer approaches for managing OA. Further research and clinical studies are warranted to optimize the utilization of MSCs and realize their full potential in the field of OA therapeutics.

Human Adipose-derived Stem Cells Upregulate IGF-1 and Alleviate Osteoarthritis in a Two-stage Rabbit Osteoarthritis Model.

OBJECTIVE: In recent years, it has been known that mesenchymal stem cells (MSCs) have the potential to treat osteoarthritis (OA). This study aimed to investigate the effects of intraarticular injection of human adipose-derived stem cells (hADSCs) in a new double-damage rabbit osteoarthritis model. METHODS: The OA model was established surgically first by medial collateral ligament and anterior insertional ligament transection and medical meniscectomy, then by articular cartilage full-thickness defect. At six weeks following surgery, hADSCs were labeled with Enhanced Green Fluorescence Protein expressing lentivirus FG12 and injected into the knee joints. All rabbits were sacrificed at 4- and 8 weeks post-surgery. Assessments were carried out by macroscopic examination, immunohistochemistry staining, magnetic resonance imaging, qRT-PCR and ELISA analysis. RESULTS: At 4- and 8 weeks, hADSCs injection showed less cartilage loss, few fissures and few cracks, decreased volume of joint effusion and cartilage defect measured with MRI. Furthermore, ELISA and qRT-PCR methods showed that hADSCs treatment increased the level of IGF-1. CONCLUSIONS: Our data suggest that hADSC transplantation promotes articular cartilage healing in the double-damage rabbit osteoarthritis model, IGF-1 may play an essential role in the hADSC-based cartilage repair process. Transplantation of hADSCs may be suitable for clinical application in the treatment of osteoarthritis.

Inhibiting the MAPK pathway improves heart failure with preserved ejection fraction induced by salt-sensitive hypertension.

Heart failure (HF) preserved ejection fraction (HFpEF) accounts for almost 50% of HF, and hypertension is one of the pathogenies. The MAPK signaling pathway is closely linked to heart failure and hypertension; however, its function in HEpEF resulting from salt-sensitive hypertension is not well understood. In this work, a salt-sensitive hypertension-induced HEpEF model was established based on deoxycorticosterone acetate-salt (DOCA-salt) hypertension mice. The impact of the MAPK inhibitor (Doramapimod) on HEpEF induced by salt-sensitive hypertension was assessed through various measures, such as blood pressure, transthoracic echocardiography, running distance, and histological analysis, to determine its therapeutic effectiveness on cardiac function. In addition, the effects of high salt on myogenic cells were also evaluated in vitro using qRTPCR. The LV ejection fractions (LVEF) in DOCA-salt hypertension mice were over 50%, indicating that the salt-sensitive hypertension-induced HFpEF model was successful. RNA-seq revealed that the MAPK signaling pathway was upregulated in the HFpEF model compared with the normal mice, accompanied by hypertension, impaired running distance, restricted cardiac function, increased cross-sectional and fibrosis area, and upregulation of heart failure biomarkers, including GAL-3, LDHA and BNP. The application of Doramapimod could improve blood pressure, cardiomyocyte hypertrophy, and myocardial fibrosis, as well as decrease the aforementioned heart failure biomarkers. The qRTPCR results showed similar findings to these observations. Our findings suggest that the use of a MAPK inhibitor (Doramapimod) could be a potential treatment for salt-sensitive hypertension-induced HFpEF.

In silico analysis and verification of critical genes related to vascular calcification in multiple diseases.

Identifying a functional molecular therapeutic target of vascular calcification (VC) that will not affect normal osteogenic differentiation is a challenge. To address this aim, we screened the differentially expressed genes (DEGs) in different VC conditions, including endothelial-osteogenic transition (EOT) (GSE167962), chronic kidney disease (CKD), and atherosclerosis (AS) (GSE159832). KEGG pathways, protein-protein interactions, and hub genes were also analyzed. The intersecting DEGs among the EOT, CKD, and AS groups were verified by quantitative reverse transcription polymerase chain reaction and immunohistochemistry in a DOCA-salt hypertension mouse model. The phosphoinositide 3-kinase-protein kinase B signaling pathway, ECM-receptor interaction, chemokine signaling pathway, and focal adhesion were enriched in EOT and AS-induced VC. ECM-receptor interaction, PPAR signaling pathway, apelin signaling pathway, AMPK signaling pathway, adipocytokine signaling pathway, and cholesterol metabolism were enriched in CKD and AS-induced VC. C4b, Cebpa, Lyz2, and Spp1 were also upregulated in EOT, CKD, AS, and hypertension. This study identified promising molecular targets for VC therapy.

Hollow silver-gold alloy nanoparticles for enhanced photothermal/photodynamic synergetic therapy against bacterial infection and acceleration of wound healing.

Bacterial infection seriously restricts the wound healing process due to severe inflammation and delayed wound healing. Unfortunately, the overuse or improper use of antibiotics leads to the advent of multidrug-resistant strains and intractable biofilms, severely affecting the therapeutic effect. Therefore, there is an urgent need to develop antibiotic-free strategies to accelerate the healing process of wounds with bacterial infection. Considering that single photothermal therapy (PTT) or photodynamic therapy (PDT) cannot fully meet the requirements of clinical sterilization and accelerating wound healing, herein, hollow silver-gold alloy nanoparticles immobilized with the photosensitizer molecule Ce6 (Ag@Au-Ce6 NPs) integrated with PTT and PDT are proposed for killing bacteria and accelerating wound healing. The photothermal conversion properties of Ag@Au-Ce6 NPs are obtained using an infrared thermal imager, and the generation of singlet oxygen (1O2) is verified with an 1O2 fluorescent probe DCFH-DA. Manipulated by near-infrared laser triggered mild hyperthermia and limited ROS amount, Ag@Au-Ce6 NPs could effectively kill bacteria that are free and colonized on the surface of wounded skin, promoting epithelium migration and vascularization, further accelerating wound healing, which showed great promise for biomedical application.

Fluorescence labeling of extracellular vesicles for diverse bio-applications in vitro and in vivo.

Extracellular vesicles (EVs) are nanosized vesicles enclosed in a lipid membrane that are sustainably released by nearly all cell types. EVs have been deemed as valuable biomarkers for diagnostics and effective drug carriers, owing to the physiological function of transporting biomolecules for intercellular communication. To investigate their biological properties, efficient labeling strategies have been constructed for EV research, among which fluorescence labeling exerts a powerful function due to the capability of visualizing the nanovesicles with high sensitivity both in vitro and in vivo. In one aspect, with the help of functional fluorescence tags, EVs could be differentiated and categorized in vitro by various analytical techniques, which exert vital roles in disease diagnosis, prognosis, and treatment monitoring. Additionally, innovative EV reporters have been utilized for visualizing EVs, in combination with powerful microscopy techniques, which provide potential tools for investigating the dynamic events of EV release and intercellular communication in suitable animal models. In this feature article, we survey the latest advances regarding EV fluorescence labeling strategies and their application in biomedical application and in vivo biology investigation, highlighting the progresses in individual EV imaging. Finally, the challenges and future perspectives in unravelling EV physiological properties and further biomedical application are discussed.

The function of guanylate binding protein 3 (GBP3) in human cancers by pan-cancer bioinformatics.

As a guanylate binding protein (GBPs) member, GBP3 is immune-associated and may participate in oncogenesis and cancer therapy. Since little has been reported on GBP3 in this field, we provide pan-cancer bioinformatics to investigate the role of GBP3 in human cancers. The GBP3 expression, related clinical outcomes, immune infiltrates, potential mechanisms and mutations were conducted using tools including TIMER2.0, GEPIA2.0, SRING, DAVID and cBioPortal. Results showed an increased risk of high GBP3 in Brain Lower Grade Glioma (LGG) and Lung Squamous Cell Carcinoma (LUSC) and a decreased risk of GBP3 in Sarcoma (SARC) and Skin Cutaneous Melanoma (SKCM) (p ≤ 0.05). GBP3 was negatively correlated with CAFs in Esophageal Adenocarcinoma (ESCA) and positively correlated with CAFs in LGG, LUSC and TGCG (p ≤ 0.05). In addition, GBP3 was positively correlated with CD8+ T cells in Bladder Urothelial Carcinoma (BLCA), Cervical Squamous Cell Carcinoma (CESC), Kidney Renal Clear Cell Carcinoma (KIRC), SARC, SKCM, SKCM-Metastasis and Uveal Melanoma (UVM) (p ≤ 0.05). Potentially, GBP3 may participate in the homeostasis between immune and adaptive immunity in cancers. Moreover, the most frequent mutation sites of GBP3 in cancers are R151Q/* and K380N. This study would provide new insight into cancer prognosis and therapy.

Salt Restriction and Angiotensin-Converting Enzyme Inhibitor Improve the Responsiveness of the Small Artery in Salt-Sensitive Hypertension.

For salt-sensitive hypertension (SSH), salt restriction and angiotensin-converting enzyme (ACE) inhibitors are essential treatments, but their effect on the function of resistance arteries is unclear. Here, we present an intravital study to detect the effect of salt restriction and ACE inhibitors on the function of the mesenteric small artery (MSA) in SSH. Dahl salt-sensitive rats were randomized into the following groups: ACE inhibitor gavage, salt restriction, ACE inhibitor combined with salt restriction, and high-salt diet. After a 12-week intervention, the mesenteric vessels maintained their perfusion in vivo, and the changes in the diameter and blood perfusion of the MSAs to norepinephrine (NE) and acetylcholine (ACh) were detected. Switching from a high-salt diet to a low-salt diet (i.e., salt restriction) attenuated the vasoconstriction of the MSAs to NE and promoted the vasodilatation to ACh, while ACE inhibitor improved the vasodilatation more obviously. Pathologically, changes in local ACE, AT1R, and eNOS expression were involved in these processes induced by a high-salt diet. Our study suggests that salt restriction and ACE inhibitor treatment improve high salt intake-induced MSA dysfunction in SSH, and salt restriction is a feasible and effective treatment. Our findings may provide a scientific basis for the treatment of hypertension.

Retraction: The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs).

Retraction of 'The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs)' by Xianfang Jiang et al., Biomater. Sci., 2018, 6, 1556-1568, https://doi.org/10.1039/C8BM00317C.

A nitric oxide responsive AIE probe for detecting the progression of osteoarthritis.

Nitric oxide (NO) is reported to be elevated in osteoarthritis (OA) both in vitro and in vivo and may be adopted to develop fluorescent probes for detecting the progression of OA. Here we report a nitric oxide responsive aggregation induced emission (AIE) probe TPE-2NHCOCH2CH2-(PEG)24-NH-Diacerein, which is derived from tetraphenylethene (TPE) modified with the hydrophilic group long poly(ethylene glycol) chain and an anti-inflammatory drug diacerein. o-Phenylenediamine within its structure can react with NO to form benzotriazole and emit fluorescence. The results show that the NO-responsive AIE probe can smartly monitor the progression of OA with the change of fluorescence intensity in vitro and in vivo. This study may provide a new development direction for early OA monitoring in clinics.

Calcium-to-phosphorus releasing ratio affects osteoinductivity and osteoconductivity of calcium phosphate bioceramics in bone tissue engineering.

Calcium phosphate (Ca-P) bioceramics, including hydroxyapatite (HA), biphasic calcium phosphate (BCP), and beta-tricalcium phosphate (ß-TCP), have been widely used in bone reconstruction. Many studies have focused on the osteoconductivity or osteoinductivity of Ca-P bioceramics, but the association between osteoconductivity and osteoinductivity is not well understood. In our study, the osteoconductivity of HA, BCP, and ß-TCP was investigated based on the osteoblastic differentiation in vitro and in situ as well as calvarial defect repair in vivo, and osteoinductivity was evaluated by using pluripotent mesenchymal stem cells (MSCs) in vitro and heterotopic ossification in muscles in vivo. Our results showed that the cell viability, alkaline phosphatase activity, and expression of osteogenesis-related genes, including osteocalcin (Ocn), bone sialoprotein (Bsp), alpha-1 type I collagen (Col1a1), and runt-related transcription factor 2 (Runx2), of osteoblasts each ranked as BCP > ß-TCP > HA, but the alkaline phosphatase activity and expression of osteogenic differentiation genes of MSCs each ranked as ß-TCP > BCP > HA. Calvarial defect implantation of Ca-P bioceramics ranked as BCP > ß-TCP ≥ HA, but intramuscular implantation ranked as ß-TCP ≥ BCP > HA in vivo. Further investigation indicated that osteoconductivity and osteoinductivity are affected by the Ca/P ratio surrounding the Ca-P bioceramics. Thus, manipulating the appropriate calcium-to-phosphorus releasing ratio is a critical factor for determining the osteoinductivity of Ca-P bioceramics in bone tissue engineering.

Unveiling the Time Course Mechanism of Bone Fracture Healing by Transcriptional Profiles.

BACKGROUND: Bone fracture healing is a time-consuming and high-priority orthopedic problem worldwide. OBJECTIVE: Discovering the potential mechanism of bone healing at a time course and transcriptional level may better help manage bone fracture. METHODS: In this study, we analyze a time-course bone fracture healing transcriptional dataset in a rat model (GSE592, GSE594, and GSE1371) of Gene Expression Omnibus (GEO). RNA was obtained from female Sprague-Dawley rats with a femoral fracture at the initial time (day 3) as well as early (week 1), middle (week 2), and late (week 4) time periods, with nonfracture rats used as control. Gene Ontology (GO) functional analysis and pathway examinations were performed for further measurements of GSEA and hub genes. RESULTS: Results indicated that the four stages of bone fracture healing at the initial, early, middle, and late time periods represent the phases of hematoma formation, callus formation, callus molding, and mature lamellar bone formation, respectively. Extracellular organization was positively employed throughout the four stages. At the hematoma formation phase, the muscle contraction process was downregulated. Antibacterial peptide pathway was downregulated at all phases. The upregulation of Fn1 (initial, early, middle, and late time periods), Col3a1 (initial, early, and middle time periods), Col11a1 (initial and early time periods), Mmp9 (middle and late time periods), Mmp13 (early, middle, and late time periods) and the downregulation of RatNP-3b (initial, early, middle, and late time periods) were possible symbols for bone fracture healing and may be used as therapeutic targets. CONCLUSION: These findings suggest some new potential pathways and genes in the process of bone fracture healing and further provide insights that can be used in targeted molecular therapy for bone fracture healing.

Identification of the genetic central dogma in osteogenic differentiation of MSCs by osteoinductive medium from transcriptional data sets.

Background: The genetic central dogma (GCD) has been demonstrated its essential function in many biological processes and diseases. However, its roles in the process of osteogenic differentiation of mesenchymal stem cells (MSCs) remain unclear. Methods: In this project, we analyzed an online database of osteogenic differentiation of MSCs after 14 days and 28 days by osteoinductive medium (GSE83770). The differentially expressed genes were screened by GEO2R, with further conducting of KEGG pathways using DAVID. In addition, protein-protein interactions of the enriched pathways were performed using STRING with marked hub genes measured by the CytoHubba. Hub genes were verified by quantitative reverse-transcription polymerase chain reaction. Results: Results showed that six pathways related to GCD, including DNA replication, Aminoacyl-tRNA biosynthesis, Mismatch repair, Ribosome, Spliceosome, and RNA degradation pathways enriched in the early stage (14 days vs. undifferentiated MSCs) of osteogenesis. The Lysosome pathway was highly enriched in the late stage (28 vs. 14 days) of osteogenesis, and Ribosome pathway plays a key role throughout the entire process (28 days vs. undifferentiated MSCs) of osteogenesis. Conclusion: Both DNA replication and protein translation were functionally worked in the early stage of osteogenesis, whereas the Lysosome pathway was the only GCD-related one in the late stage of osteogenesis. The GCD-related Ribosome pathway occupied the entire process of osteogenesis.

Emulating interactions between microorganisms and tumor microenvironment to develop cancer theranostics.

The occurrence of microorganisms has been confirmed in the tumor microenvironment (TME) of many different organs. Microorganisms (e.g., phage, virus, bacteria, fungi, and protozoa) present in TME modulate TME to inhibit or promote tumor growth in species-dependent manners due to the special physiological and pathological features of each microorganism. Such microorganism-TME interactions have recently been emulated to turn microorganisms into powerful cancer theranostic agents. To facilitate scientists to explore microorganisms-TME interactions further to develop improved cancer theranostics, here we critically review the characteristics of different microorganisms that can be found in TME, their interactions with TME, and their current applications in cancer diagnosis and therapy. Clinical trials of using microorganisms for cancer theranostics are also summarized and discussed. Moreover, the emerging technology of whole-metagenome sequencing that can be employed to precisely determine microbiota spectra is described. Such technology enables scientists to gain an in-depth understanding of the species and distributions of microorganisms in TME. Therefore, scientists now have new tools to identify microorganisms (either naturally present in or introduced into TME) that can be used as effective probes, monitors, vaccines, or drugs for potentially advancing cancer theranostics to clinical applications.

Construction of tissue-customized hydrogels from cross-linkable materials for effective tissue regeneration.

Hydrogels are prevalent scaffolds for tissue regeneration because of their hierarchical architectures along with outstanding biocompatibility and unique rheological and mechanical properties. For decades, researchers have found that many materials (natural, synthetic, or hybrid) can form hydrogels using different cross-linking strategies. Traditional strategies for fabricating hydrogels include physical, chemical, and enzymatical cross-linking methods. However, due to the diverse characteristics of different tissues/organs to be regenerated, tissue-customized hydrogels need to be developed through precisely controlled processes, making the manufacture of hydrogels reliant on novel cross-linking strategies. Thus, hybrid cross-linkable materials are proposed to tackle this challenge through hybrid cross-linking strategies. Here, different cross-linkable materials and their associated cross-linking strategies are summarized. From the perspective of the major characteristics of the target tissues/organs, we critically analyze how different cross-linking strategies are tailored to fit the regeneration of such tissues and organs. To further advance this field, more appropriate cross-linkable materials and cross-linking strategies should be investigated. In addition, some innovative technologies, such as 3D bioprinting, the internet of medical things (IoMT), and artificial intelligence (AI), are also proposed to improve the development of hydrogels for more efficient tissue regeneration.

Injectable calcium phosphate ceramics prevent osteoclastic differentiation and osteoporotic bone loss: Potential applications for regional osteolysis.

Calcium phosphates (CaPs) in the form of blocks are typically not satisfied for administration to osteoporotic patients because of their rapid resorption rate in vivo. However, injectable CaP powders have not been investigated for their potential in osteoporotic hosts. Herein, CaPs in the form of nanoparticles was reported can inhibit RANKL-stimulated osteoclastic differentiation (OC) and bone resorption, as evidenced by suppressed TRAP-positive cells, disintegrated F-actin rings and downregulated expression of markers for OC. CaP powders also significantly inhibited nuclear factor-κB (NF-κB) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) activation. Furthermore, injectable CaPs reversed bone loss in a mouse model induced by lipopolysaccharide (LPS) and promoted osteoblastic formation in the absent of pro-osteogenic agents. Therefore, injectable CaPs, especially biphasic calcium phosphate (BCP), could be developed as novel agents for the therapy of osteolysis-related diseases caused by inflammation.

A dual PMMA/calcium sulfate carrier of vancomycin is more effective than PMMA-vancomycin at inhibiting Staphylococcus aureus growth in vitro.

Both antibiotic-impregnated poly(methyl acrylate, methyl methacrylate) (PMMA) and antibiotic-impregnated calcium sulfate have been successfully used as local antibiotic delivery vehicles for the management of chronic osteomyelitis. Here, we examined the antibiotic elution characteristics and antibacterial properties of a composite drug delivery system consisting of PMMA/calcium sulfate carrying vancomycin (dual carrier-v) against Staphylococcus aureus, with PMMA loaded with vancomycin (PMMA-v) as a control. Vancomycin gradually degraded from dual carrier-v and PMMA-v up to about 8 and 6 weeks, respectively. At different elution time points, the inhibition zones of the dual carrier-v were larger than the inhibition zones of the PMMA-v (P < 0.05). The colony inhibition rate of the dual carrier-v was 95.57%, whereas it was 77.87% for PMMA-v. Scanning electron microscopy was used to demonstrate biofilm formation on the surface of plates treated with vancomycin-unloaded PMMA, whereas there was no biofilm formation on the surface of plates treated with dual carrier-v or PMMA-v. The dual carrier-v was more effective at antibacterial adhesion at each time point after immersion in simulated body fluid as compared with PMMA-v (P < 0.05). In conclusion, our results suggest that the dual carrier-v can release higher concentrations of antibiotics and inhibit bacteria growth more effectively in vitro as compared with PMMA-v. The dual carrier-v thus may have potential as an alternative strategy for osteomyelitis management.

Syndecan-4 involves in the pathogenesis of rheumatoid arthritis by regulating the inflammatory response and apoptosis of fibroblast-like synoviocytes.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease, and the pathogenesis of RA is still unknown. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) are of significance in the pathogenesis of RA. In this study, three microarray profiles (GSE55457, GSE55584, and GSE55235) of human joint FLSs from 33 RA patients and 20 normal controls were extracted from the Gene Expression Omnibus Dataset and analyzed to investigate the underlying pathogenesis of RA. As analyzed by the differently expressed genes, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, and protein-protein interaction network analysis, syndecan-4 (SDC4), a receptor of multiple cytokines and chemokines, which played a key role in the regulation of inflammatory response, was found to be an essential regulator in RA. To further validate these results, the levels of SDC4, reactive oxygen species (ROS), nitric oxide (NO), inflammation, and apoptosis in RA-FLSs were examined. SDC4-silenced RA-FLSs were also used. The results demonstrated that SDC4 and the level of ROS, NO, and inflammation were highly expressed while the apoptosis was decreased in RA-FLSs compared with normal FLSs. SDC4 silencing significantly suppressed the levels of ROS, NO, and inflammation; elevated the expression of nuclear factor erythroid 2-related factor 2; and promoted the apoptosis of RA-FLSs. Collectively, our results demonstrated a new mechanism of SDC4 in initiating the inflammation and inhibiting the apoptosis of RA-FLSs and that a potential target for the diagnosis and treatment of RA in the clinic might be developed.