P7C3 Ameliorates Bone Loss by Inhibiting Osteoclast Differentiation and Promoting Osteogenesis.

Bone homeostasis, the equilibrium between bone resorption and formation, is essential for maintaining healthy bone tissue in adult humans. Disruptions of this process can lead to pathological conditions such as osteoporosis. Dual-targeted agents, capable of inhibiting excessive bone resorption and stimulating bone formation, are being explored as a promising strategy for developing new treatments to address osteoporosis. In this study, we investigated the effects of P7C3 on bone remodeling and its potential therapeutic role in osteoporosis treatment in mice. Specifically, P7C3 can remarkably suppress receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL)-induced osteoclast differentiation in bone marrow macrophages via the Akt-NF-κB-NFATc1 signaling pathway. Additionally, RNA sequencing (RNAseq) analysis revealed that P7C3 promoted osteoblast differentiation and function through the Wnt/ß-catenin signaling pathway, thereby enhancing bone formation. Furthermore, µCT analysis and histological examination of bone tissues from P7C3-treated mice showed attenuation of both Ti-induced bone erosion and ovariectomy (OVX)-induced bone loss. These findings suggest that P7C3 may have a novel function in bone remodeling and may be a promising therapeutic agent for the treatment of osteoporosis. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Real-world efficacy of belimumab in systemic lupus erythematosus: a prospective cohort from a single center in China.

OBJECTIVES: To explore the efficacy and safety of belimumab among Chinese patients with systemic lupus erythematosus (SLE) in a real-world setting. METHODS: A prospective cohort study was performed, and SLE patients taking belimumab on a background of standard-of-care (SoC) treatment were consecutively enrolled from June 2021 to December 2022. Based on baseline characteristics, patients were divided into three groups: the newly diagnosed group, the relapsed group and the refractory group. Patients in the newly diagnosed group were newly diagnosed with SLE within 4 weeks of starting belimumab. Patients in the relapse group experienced a severe flare. Refractory patients were patients with unsatisfactory glucocorticoid taper and/or disease activity control. Clinical data were collected, and disease assessments were conducted regularly. Newly diagnosed patients with SoC alone and healthy controls (HCs) were also enrolled. RESULTS: A total of 123 SLE patients were included in the analysis, with a median follow-up period of 12 months (range 3-18 months). Thirty-three out of 123 patients were newly diagnosed, 32 had relapsed disease, and 58 had refractory disease. The SRI-4 response was achieved with good tolerance by 55.77% of patients at 3 months, 56.63% at 6 months, 63.24% at 9 months, 63.64% at 12 months, and 57.14% at 18 months. Serological parameters (anti-dsDNA and C3/C4), SLEDAI-2K and daily prednisone intake were improved overall and in each group. Among the 3 groups, the newly diagnosed group had the highest SRI-4 rate as well as the greatest improvement in serological parameters and SLEDAI-2K. Compared with newly diagnosed patients with SoC alone, the cumulative prednisone intake of newly diagnosed patients taking belimumab was significantly decreased. CONCLUSION: Our data supported the efficacy of belimumab in Chinese SLE patients in a real-life setting. Our study also provided new evidence showing remarkable achievement of the SRI-4 response during belimumab treatment in newly diagnosed SLE patients.

Matrix Stiffness Activating YAP/TEAD1-Cyclin B1 in Nucleus Pulposus Cells Promotes Intervertebral Disc Degeneration.

Intervertebral disc degeneration is a leading cause of disability in the elderly population. Rigid extracellular matrix is a critical pathological feature of disc degeneration, leading to aberrant nucleus pulposus cells (NPCs) proliferation. However, the underlying mechanism is unclear. Here, we hypothesize that increased matrix stiffness induces proliferation and thus degenerative phenotypes of NPCs through YAP/TEAD1 signaling pathway. We established hydrogel substrates to mimic stiffness of degenerated human nucleus pulposus tissues. RNA-sequencing identified differentially expressed genes between primary rat NPCs cultured on rigid and soft hydrogels. Dual luciferase assay and gain- and loss-function experiments evaluated the correlation between YAP/TEAD1 and Cyclin B1. Furthermore, single-cell RNA-sequencing of human NPCs was performed to identify specific cell clusters with high YAP expression. Matrix stiffness increased in severely degenerated human nucleus pulposus tissues (p < 0.05). Rigid substrate enhanced rat NPCs proliferation mainly through Cyclin B1, which was directly targeted and positively regulated by YAP/TEAD1. Depletion of YAP or Cyclin B1 arrested G2/M phase progression of rat NPCs and reduced fibrotic phenotypes including MMP13 and CTGF (p < 0.05). Fibro NPCs with high YAP expression were identified in human tissues and responsible for fibrogenesis during degeneration. Furthermore, inhibition of YAP/TEAD interaction by verteporfin suppressed cell proliferation and alleviated degeneration in the disc needle puncture model (p < 0.05). Our results demonstrate that elevated matrix stiffness stimulates fibro NPCs proliferation through YAP/TEAD1-Cyclin B1 axis, indicating a therapeutic target for disc degeneration.

A Feedback Loop of LINC00665 and the Wnt Signaling Pathway Expedites Osteosarcoma Cell Proliferation, Invasion, and Epithelial-Mesenchymal Transition.

OBJECTIVES: Osteosarcoma (OS) is a malignant tumor with frequent occurrence among teenagers. Long non-coding RNAs (lncRNAs) play pro-cancer roles in many tumors. The purpose of this study was to figure out the functional role of a novel lncRNA long intergenic non-protein coding RNA 665 (LINC00665) in OS by observing the OS cell behaviors. METHODS: Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to analyze LINC00665 expression in OS cells. Cell function assays assessed the impacts of LINC00665 on OS cell phenotype. Immunofluorescence and western blot analyzed the function of LINC00665 on epithelial-mesenchymal transition (EMT) in OS. Moreover, mechanistic assays analyzed the downstream mechanism of LINC00665 in OS cells. RESULTS: LINC00665 was significantly up-regulated in OS cells. LINC00665 silence facilitated OS cell proliferation, migration, invasion, and EMT while inhibiting cell apoptosis. Mechanically, LINC00665 acted as a competing endogenous RNA (ceRNA) to sponge miR-1249-5p and thereby modulated Wnt family member 2B (WNT2B) to activate Wnt pathway. Wnt pathway activated LINC00665 expression transcriptionally. CONCLUSIONS: Our study uncovered the cancer-promoting role of LINC00665 in OS, and the feedback loop of LINC00665/miR-1249-5p/WNT2B/Wnt might be a potential target for OS treatment.

Habitual intakes of sugar-sweetened beverages associated with gut microbiota-related metabolites and metabolic health outcomes in young Chinese adults.

BACKGROUND AND AIMS: Reducing consumption of sugar-sweetened beverages (SSBs) is a global public health priority because of their limited nutritional value and associations with increased risk of obesity and metabolic diseases. Gut microbiota-related metabolites emerged as quintessential effectors that may mediate impacts of dietary exposures on the modulation of host commensal microbiome and physiological status. METHODS AND RESULTS: This study assessed the associations among SSBs, circulating microbial metabolites, and gut microbiota-host co-metabolites, as well as metabolic health outcomes in young Chinese adults (n = 86), from the Carbohydrate Alternatives and Metabolic Phenotypes study in Shaanxi Province. Five principal component analysis-derived beverage drinking patterns were determined on self-reported SSB intakes, which were to a varying degree associated with 143 plasma levels of gut microbiota-related metabolites profiled by untargeted metabolomics. Moreover, carbonated beverages, fruit juice, energy drinks, and bubble tea exhibited positive associations with obesity-related markers and blood lipids, which were further validated in an independent cohort of 16,851 participants from the Regional Ethnic Cohort Study in Northwest China in Shaanxi Province. In contrast, presweetened coffee was negatively associated with the obesity-related traits. A total of 79 metabolites were associated with both SSBs and metabolic markers, particularly obesity markers. Pathway enrichment analysis identified the branched-chain amino acid catabolism and aminoacyl-tRNA biosynthesis as linking SSB intake with metabolic health outcomes. CONCLUSION: Our findings demonstrate the associations between habitual intakes of SSBs and several metabolic markers relevant to noncommunicable diseases, and highlight the critical involvement of gut microbiota-related metabolites in mediating such associations.

Genetically Engineered Hematopoietic Stem Cells Deliver TGF-ß Inhibitor to Enhance Bone Metastases Immunotherapy.

Owing to the immune microenvironment of bones and low selectivity of the drug, patients with bone metastases often respond poorly to immunotherapy. In this study, programmed cell death protein 1 (PD1)-expressing hematopoietic stem cells (HSCs) are genetically engineered for bone-targeted delivery of the transforming growth factor beta (TGF-ß) small-molecule inhibitor SB-505124 (SB@HSCs-PD-1). Intriguingly, compared to anti-PD-L1 monoclonal antibodies, as "living drugs", HSCs-PD-1 not only show great targeting ability to the bone marrow, but are also able to reduplicate themselves within the bone marrow niche and continuously express PD-1 molecules. The SB released from HSCs-PD-1 competitively bound to TGF-ß receptors on CD4+ T cells and facilitate CD4+ T cell differentiation to helper T (TH )1 and TH 2 cells, thereby reprogramming the local immunosuppressive milieu of the bone marrow. Additionally, HSCs-PD-1 can block programmed death-ligand 1 on tumor and myeloid cells, resulting in reinvigorated anti-tumor immunity of T cells. In conclusion, in the present study, an alternative cell engineering strategy is delineated for immune checkpoint blockade therapy, to target bone metastasis using HSCs as a platform, which shows great promise in the treatment of bone metastases.

Four-octyl itaconate improves osteoarthritis by enhancing autophagy in chondrocytes via PI3K/AKT/mTOR signalling pathway inhibition.

Osteoarthritis (OA) is a highly prevalent and chronic disorder that is associated with a substantial social and economic burden. Itaconate, as an important regulator of cellular inflammation, is a metabolite synthesised by an enzyme encoded by immune-responsive gene 1. However, there are few studys regarding the effects of itaconate on OA. Here, we show the effect of the cell-permeable itaconate derivative 4-octyl itaconate (OI) on OA. OI attenuates the chondrocyte apoptosis induced by interleukin 1ß (IL-1ß) in vitro, indicating that OI protect chondrocytes against apoptosis. Moreover, OI ameliorates the chondrocyte autophagy inhibition induced by IL-1ß via the inhibition of PI3K/AKT/mTOR signalling pathway. Finally, OI enhances autophagy and reduces cartilage degradation in a rat model of OA established by destabilization of medial meniscus (DMM). In summary, our findings reveal that OI is involved in regulating the progression of OA. The above results shed light on the treatment of OA.

Gold nanorods modified by endogenous protein with light-irradiation enhance bone repair via multiple osteogenic signal pathways.

Fracture is one of the most common clinical diseases that reduce the quality of patients' lives significantly. In this study, we prepared gold nanorods modified by endogenous proteins which collected from the autologous blood of individual mice for enhanced photothermal therapy (PTT) to treat fracture. Due to the outermost layer being endogenous proteins, we find that GNRs neither activate the immune cells in vitro nor cause any rejection immune responses after entering the body as compared with PEG modification. In addition, the internal bleeding and edema of the fracture site result in a rapid enrichment of GNRs after intravenous injection. Under near infrared (NIR) light irradiation, the mild photothermal effect of the accumulated GNRs can effectively promote healing of fracture in mice. The molecular mechanism of osteogenic capability is revealed by transcriptome sequencing and subsequent confirmatory experiments, indicating enhanced two key osteogenic signal transduction (MAPK, PI3K-Akt) and multiple key osteogenesis related factors expression following the treatment. Our strategy offers an alternative way to promote bone regeneration following a fracture.

Yeast-derived nanoparticles remodel the immunosuppressive microenvironment in tumor and tumor-draining lymph nodes to suppress tumor growth.

Microbe-based cancer immunotherapy has recently emerged as a hot topic for cancer treatment. However, serious limitations remain including infection associated side-effect and unsatisfactory outcomes in clinic trials. Here, we fabricate different sizes of nano-formulations derived from yeast cell wall (YCW NPs) by differential centrifugation. The induction of anticancer immunity of our formulations appears to inversely correlate with their size due to the ability to accumulate in tumor-draining lymph node (TDLN). Moreover, we use a percolation model to explain their distribution behavior toward TDLN. The abundance and functional orientation of each effector component are significantly improved not only in the microenvironment in tumor but also in the TDLN following small size YCW NPs treatment. In combination with programmed death-ligand 1 (PD-L1) blockade, we demonstrate anticancer efficiency in melanoma-challenged mice. We delineate potential strategy to target immunosuppressive microenvironment by microbe-based nanoparticles and highlight the role of size effect in microbe-based immune therapeutics.

Amlodipine Improves Spinal Cord Injury Repair by Inhibiting Motoneuronal Apoptosis Through Autophagy Upregulation.

STUDY DESIGN: The effect of amlodipine (AM) on spinal cord injury (SCI) and autophagy was researched by establishing ventral spinal cord cells (VSC4.1) oxygen and glucose deprivation model and SCI mice model. OBJECTIVE: To determine the neuroprotective effects of AM by upregulating autophagy during SCI repair. SUMMARY OF BACKGROUND DATA: AM, an antihypertensive medication, has been shown in several studies to inhibit neuronal apoptosis and exert neuroprotective effects in various central nervous system diseases. However, its effects on SCI are unexplored. Autophagy could inhibit cell apoptosis, which has been shown to promote SCI repair. However, the role of AM in autophagy remains unclear. METHODS: We examined the relationship between AM, apoptosis, and autophagy in ventral spinal cord cells and the injured spinal cords of C57BL/6 female mice respectively, following histological, behavioral, microscopic, immunofluorescence, and western blotting analyses. RESULTS: We found that AM could inhibit motor neuronal apoptosis in vitro. Furthermore, AM promoted locomotor recovery by upregulating autophagy and alleviating apoptosis, neuronal loss, and spinal cord damage after SCI. CONCLUSION: AM inhibited motoneuronal apoptosis by upregulating autophagy to improve SCI recovery.

Injectable Erythrocyte Gel Loaded with Bulleyaconitine A for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a systemic autoimmune disease with clinical manifestations including joint cartilage, synovitis, and bone damage. Here we developed an injectable erythrocyte gel loaded with Bulleyaconitine A (BLA) for the treatment of RA and demonstrated its anti-inflammatory effects in vivo and in vitro. In vitro experiments showed that BLA could effectively down-regulate the expression of pro-inflammatory factor in activated macrophages through the nuclear factor-κB (NF-κB) pathway. In vivo experiments have shown that the injection of BLA@RBCs in the inflammatory joints of CIA mice increases the local concentration of BLA in a long time. Improved therapeutic outcomes and reduced toxicity of BLA are demonstrated in our work. Together, the developed BLA@RBCs drug delivery system provides an alternative strategy to treat RA joints and shows high potential in clinical RA treatment.

Tumor-derived exosomal miR-19b-3p facilitates M2 macrophage polarization and exosomal LINC00273 secretion to promote lung adenocarcinoma metastasis via Hippo pathway.

Numerous reports have elucidated the important participation of exosomes in the communication between tumor cells and other cancer-related cells including tumor-associated macrophages (TAMs) in microenvironment. However, the interchange of exosomes between tumor cells and TAMs in the progression of lung adenocarcinoma (LUAD) remains largely enigmatic. Herein, we discovered that LUAD cells induced the M2 polarization of TAMs and the M2-polarized macrophages facilitated LUAD cell invasion and migration and tumor metastasis in vivo. In detail, LUAD cells secreted exosomes to transport miR-19b-3p into TAMs so that miR-19b-3p targeted PTPRD and inhibited the PTPRD-mediated dephosphorylation of STAT3 in TAMs, leading to STAT3 activation and M2 polarization. Also, the activated STAT3 transcriptionally induced LINC00273 in M2 macrophages and exosomal LINC00273 was transferred into LUAD cells. In LUAD cells, LINC00273 recruited NEDD4 to facilitate LATS2 ubiquitination and degradation, so that the Hippo pathway was inactivated and YAP induced the transcription of RBMX. RBMX bound to miR-19b-3p to facilitate the packaging of miR-19b-3p into LUAD cell-derived exosomes. Collectively, our results revealed the mechanism underlying the interactive communication between LUAD cells and TAMs through elucidating the exchange of exosomal miR-19b-3p and LINC00273 and proved the prometastatic effect of the interchange between two cells. These discoveries opened a new vision for developing LUAD treatment.

Injectable ROS-scavenging hydrogel with MSCs promoted the regeneration of damaged skeletal muscle.

Skeletal muscle injury is a common disease accompanied by inflammation, and its treatment still faces many challenges. The local inflammatory microenvironment can be modulated by a novel ROS-scavenging hydrogel (Gel) we constructed. And MSCs could differentiate into myoblasts and contribute to muscle tissue homeostasis and regeneration. Here, Gel loaded with mesenchymal stem cells (MSCs) (Gel@MSCs) was developed for repairing the injured skeletal muscle. Results showed that the Gel improved the survivability and enhanced the proliferation of MSCs (≈two-fold), and the Gel@MSCs inhibited the local inflammatory responses as it promoted polarization of M2 macrophages (increased from 5% to 17%), the mediator of the production of anti-inflammatory factors. Western blotting and qPCR revealed the Gel promoted the expression of proteins (≈two-fold) and genes (≈two to six-fold) related to myogenesis in MSCs. Histological assessment indicated that the Gel or MSCs promoted regeneration of skeletal muscle, and the efficacy was more significant at Gel@MSCs than MSCs alone. Finally, behavioral experiments confirmed that Gel@MSCs improved the motor function of injured mice. In short, the Gel@MSCs system we constructed presented a positive effect on reducing skeletal muscle damage and promoted skeletal muscle regeneration, which might be a novel treatment for such injuries.

Implantable blood clot loaded with BMP-2 for regulation of osteoimmunology and enhancement of bone repair.

The treatment of large-area bone defects still faces many difficulties and challenges. Here, we developed a blood clot delivery platform loaded with BMP-2 protein (BMP-2@BC) for enhanced bone regeneration. Blood clot gel platform as natural biomaterials can be engineered from autologous blood. Once implanted into the large bone defect site, it can be used for BMP-2 local delivery, as well as modulating osteoimmunology by recruiting a great number of macrophages and regulating their polarization at different stages. Moreover, due to the deep-red color of blood clot gel, mild localized hyperthermia under laser irradiation further accelerated bone repair and regeneration. We find that the immune niche within the bone defect microenvironment can be modulated in a controllable manner by the blood clots implantation and laser treatment. We further demonstrate that the newly formed bone covered almost 95% of the skull defect area by our strategy in both mice and rat disease models. Due to the great biocompatibility, photothermal potential, and osteoimmunomodulation capacity, such technology shows great promise to be used in further clinical translation.

Requirement of Gαi1 and Gαi3 in interleukin-4-induced signaling, macrophage M2 polarization and allergic asthma response.

IL-4 induces Akt activation in macrophages, required for full M2 (alternative) polarization. We examined the roles of Gαi1 and Gαi3 in M2 polarization using multiple genetic methods. Methods and Results: In MEFs and primary murine BMDMs, Gαi1/3 shRNA, knockout or dominant negative mutations attenuated IL-4-induced IL4Rα endocytosis, Gab1 recruitment as well as Akt activation, leaving STAT6 signaling unaffected. Following IL-4 stimulation, Gαi1/3 proteins associated with the intracellular domain of IL-4Rα and the APPL1 adaptor, to mediate IL-4Rα endosomal traffic and Gab1-Akt activation in BMDMs. In contrast, gene silencing of Gαi1/3 with shRNA or knockout resulted in BMDMs that were refractory to IL-4-induced M2 polarization. Conversely, Gαi1/3-overexpressed BMDMs displayed preferred M2 response with IL-4 stimulation. In primary human macrophages IL-4-induced Akt activation and Th2 genes expression were inhibited with Gαi1/3 silencing, but augmented with Gαi1/3 overexpression. In Gαi1/3 double knockout (DKO) mice, M2 polarization, by injection of IL-4 complex or chitin, was potently inhibited. Moreover, in a murine model of asthma, ovalbumin-induced airway inflammation and hyperresponsiveness were largely impaired in Gαi1/3 DKO mice. Conclusion: These findings highlight novel and essential roles for Gαi1/3 in regulating IL-4-induced signaling, macrophage M2 polarization and allergic asthma response.

Platelet-derived extracellular vesicles to target plaque inflammation for effective anti-atherosclerotic therapy.

Atherosclerosis is a kind of chronic inflammatory diseases characterized by dysfunction of local immune responses. Here we engineer platelet-derived extracellular vesicles (PEVs) to load MCC950, an NLRP3-inflammasome inhibitor, for atherosclerosis-targeted therapy. PEVs which are readily collected from the activated platelets selectively bind multiple cell types associated with the formation of atherosclerotic plaque in vivo. Intravenous administration of MCC950-PEVs could significantly reduce the formation of atherosclerotic plaques, lower the local inflammation and inhibit proliferation of macrophages and T cells at the plaque site compared with free drug administration in ApoE-KO mice. Our strategy suggests the promise of PEVs for targeted drug delivery for treatment of atherosclerosis.

Medical supplies scheduling in major public health emergencies.

In the early days of the COVID-19 pandemic in Wuhan, there was an unreasonable allocation between hospitals and a lack of timely transportation of medical supplies, which reduced the cure rate of infected cases. To solve the problem, this research proposes a method for scheduling medical supplies in major public health emergencies to develop a rapid and accurate supply scheme for medical materials, including the allocation of medical materials per vehicle to each hospital and the supply sequence per vehicle to each hospital. Specifically, this paper solves the following two sub-problems: (1) calculating the shortest transportation times and the corresponding routes from any distributing center(s) to any hospital(s); (2) calculating the medical supplies per vehicle transporting to each hospital. The method of solving sub-problem 1 is performed by multiple iterations, each of which calculates the shortest route from a distributing center, through one or more hospitals, and back to the distributing center. According to sub-problem 2, this research proposes a distribution model of medical supplies in major public health emergencies. A multiple dynamic programming algorithm which is a combination of some separated dynamic programming operations is proposed to solve this model. This algorithm also realizes the rapid updating of the scheme in the context of the changing number of vehicles. The first sub-problem can be solved in normal times, while the second one should be solved on the premise of obtaining the corresponding data after the occurrence of a major public health emergency. In the case study section, the whole method proposed in this research is employed in the medical supplies scheduling in the early stage of the COVID-19 outbreak in Wuhan, which proves the availability of the method. The main innovation of the method proposed in this research is that the problems can obtain the optimal solution while the time complexity is within an acceptable range.

Impact of energy structure on carbon emission and economy of China in the scenario of carbon taxation.

As the largest CO2 emitter in the world, China intends to achieve the peak of carbon emissions in around 2030. Unlike many other countries' targets of reducing the amount the carbon emissions, China has engaged in achieving the goal of carbon emission intensity regulation including economic development and carbon emission reduction. In recent years, carbon tax policy has been implemented by about 30 national and sub-national jurisdictions in controlling carbon emissions and has shown promising results. In this context, this research evaluates whether the carbon tax is an effective way for China to accomplish the win-win target of carbon reduction and GDP growth. Specifically, a model is established based on the energy substitution theory and input-output theory to evaluate the effectiveness of carbon tax on the eight economic sectors of China. The carbon emission reduction and economic performance before and after carbon taxation are compared. Moreover, the effects of different carbon tax rates on economic development are analyzed. The results are as follows: (1) The total amount of carbon emission decreases while the carbon tax is levied, and a positive correlation is found between the tax rate and the emission reduction amount. (2) The carbon tax has a significant impact on economic development, and a negative correlation is found between the tax rate and economic development. However, the loss of the economic output caused by the carbon tax gradually reduces over time. (3) Carbon tax policy would be effective for China to accomplish the win-win goal of carbon reduction and GDP growth. Moreover, the carbon tax rate should be set at a low level to achieve the target by the lowest economic cost. On this basis, several policy recommendations are proposed by this research.

Hepatocyte growth factor overexpression promotes osteoclastogenesis and exacerbates bone loss in CIA mice.

BACKGROUND: Hepatocyte growth factor (HGF) is a multifunctional growth factor that promotes various biological processes. However, the effect of HGF on bone metabolism in rheumatoid arthritis (RA) remains unknown. Here, we investigated the role of HGF in regulating osteoclastogenesis and bone resorption in RA. METHODS: The expression of HGF in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of HGF on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The effect of HGF inhibition was evaluated in a CIA mice model. The mechanism of HGF in regulating osteoclastogenesis and bone resorption was explored by a series of in vitro studies. RESULTS: HGF was overexpressed in CIA and RA. HGF stimulated osteoclastogenesis in vitro. SU11274, a selective small molecule blocker of c-Met, impeded the effect of HGF on osteoclastogenesis and bone resorption. HGF regulated osteoclastogenesis by JNK and AKT-GSK-3ß-NFATc1 signallings. SU11274 protected CIA mice from pathological bone loss. CONCLUSIONS: These data strongly suggest that the highly expressed HGF in the joint tissues contributes to bone loss in RA. Inhibition of HGF/c-Met could effectively alleviate pathological bone loss and inflammatory symptoms in CIA mice. HGF/c-Met may be used as a new target for the treatment of bone loss in RA.

LncRNA MM2P-induced, exosome-mediated transfer of Sox9 from monocyte-derived cells modulates primary chondrocytes.

Monocyte-derived cells were shown to promote cartilage repair in osteoarthritis. The role of the long non-coding RNA (lncRNA) MM2P in this function of monocyte-derived cells remained unexplored. Treatment of RAW264.7 murine macrophages and mouse bone marrow-derived macrophages with IL-4 or IL-13 upregulated MM2P expression, upstream of STAT3 and STAT6 phosphorylation. Specifically, MM2P blocked SHP2-mediated dephosphorylation of STAT3 at Try705 and interacted with the RNA-binding protein FUS. In turn, p-STAT3 increased the Sox9 gene expression. These cells released Sox9 mRNA and protein-containing exosomes, as demonstrated by a transmission electron microscope, nanoparticle tracking analysis, and detection of typical surface markers. Their culture supernatant promoted the differentiation of mouse primary chondrocytes, i.e., upregulated the expression of Col1a2 and Acan genes and promoted the secretion of extracellular matrix components proteoglycan and type II collagen. These effects were mediated by Sox9 mRNA and protein delivered to chondrocytes by exosomes. Together, ex vivo treatment of monocyte-derived cells with IL-4 or IL-13 promoted chondrocyte differentiation and functions through exosome-mediated delivery of Sox9 mRNA and protein.