NAMPT enhances LOX expression and promotes metastasis in human chondrosarcoma cells by inhibiting miR-26b-5p synthesis.

Chondrosarcoma is a malignant bone tumor that emerges from abnormalities in cartilaginous tissue and is related with lung metastases. Nicotinamide phosphoribosyltransferase (NAMPT) is an adipocytokine reported to enhance tumor metastasis. Our results from clinical samples and the Gene Expression Omnibus data set reveal that NAMPT levels are markedly higher in chondrosarcoma patients than in normal individuals. NAMPT stimulation significantly increased lysyl oxidase (LOX) production in chondrosarcoma cells. Additionally, NAMPT increased LOX-dependent cell migration and invasion in chondrosarcoma by suppressing miR-26b-5p generation through the c-Src and Akt signaling pathways. Overexpression of NAMPT promoted chondrosarcoma metastasis to the lung in vivo. Furthermore, knockdown of LOX counteracted NAMPT-facilitated metastasis. Thus, the NAMPT/LOX axis presents a novel target for treating the metastasis of chondrosarcoma.

Inhibiting Bruton's Tyrosine Kinase to Counteract Chemoresistance and Stem Cell-Like Properties in Osteosarcoma.

Osteosarcoma, a highly aggressive bone cancer, often develops resistance to conventional chemotherapeutics, leading to poor prognosis and survival rates. The malignancy and chemoresistance of osteosarcoma pose significant challenges in its treatment, highlighting the critical need for novel therapeutic approaches. Bruton's tyrosine kinase (BTK) plays a pivotal role in B-cell development and has been linked to various cancers, including breast, lung, and oral cancers, where it contributes to tumor growth and chemoresistance. Despite its established importance in these malignancies, the impact of BTK on osteosarcoma remains unexplored. Our study delves into the expression levels of BTK in osteosarcoma tissues by data from the GEO and TCGA database, revealing a marked increase in BTK expression compared with primary osteoblasts and a potential correlation with primary site progression. Through our investigations, we identified a subset of osteosarcoma cells, named cis-HOS, which exhibited resistance to cisplatin. These cells displayed characteristics of cancer stem cells (CSCs), demonstrated a higher angiogenesis effect, and had an increased migration ability. Notably, an upregulation of BTK was observed in these cisplatin-resistant cells. The application of ibrutinib, a BTK inhibitor, significantly mitigated these aggressive traits. Our study demonstrates that BTK plays a crucial role in conferring chemoresistance in osteosarcoma. The upregulation of BTK in cisplatin-resistant cells was effectively countered by ibrutinib. These findings underscore the potential of targeting BTK as an effective strategy to overcome chemoresistance in osteosarcoma treatment.

The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Extracellular vesicles called exosomes are primarily used as mediators of intercellular signal transmission to control tumor metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with exosome generation in chondrosarcoma motility remains undetermined. Our results found that overexpressing visfatin augments the production of exosomes from chondrosarcoma cells. Visfatin-treated chondrosarcoma exosomes educate macrophage polarization towards the M2 but not M1 phenotype. Interestingly, M2 macrophages polarized by exosomes return to chondrosarcoma cells to facilitate cell motility. According to these findings, chondrosarcoma cells emit more exosomes when treated with visfatin. The stimulation of exosome generation by visfatin polarizes M2 macrophages and enhances the motility of chondrosarcoma.

Visfatin Facilitates VEGF-D-Induced Lymphangiogenesis through Activating HIF-1α and Suppressing miR-2277-3p in Human Chondrosarcoma.

Chondrosarcoma is a malignant bone tumor that arises from abnormalities in cartilaginous tissue and is associated with lung metastases. Lymphangiogenesis plays an essential role in cancer metastasis. Visfatin is an adipokine reported to enhance tumor metastasis, but its relationship with VEGF-D generation and lymphangiogenesis in chondrosarcoma remains undetermined. Our results from clinical samples reveal that VEGF-D levels are markedly higher in chondrosarcoma patients than in normal individuals. Visfatin stimulation promotes VEGF-D-dependent lymphatic endothelial cell lymphangiogenesis. We also found that visfatin induces VEGF-D production by activating HIF-1α and reducing miR-2277-3p generation through the Raf/MEK/ERK signaling cascade. Importantly, visfatin controls chondrosarcoma-related lymphangiogenesis in vivo. Therefore, visfatin is a promising target in the treatment of chondrosarcoma lymphangiogenesis.

Melatonin inhibits chondrosarcoma cell proliferation and metastasis by enhancing miR-520f-3p production and suppressing MMP7 expression.

Chondrosarcoma has a high propensity to metastasize and responds poorly to chemotherapy and radiation treatment. The enzymatic activity of matrix metalloproteinases (MMPs) is very important in chondrosarcoma metastasis. Melatonin exhibits anticarcinogenic activity in many types of cancers by suppressing the expression of certain MMP family members, but this has not yet been clearly determined in chondrosarcoma. Our study demonstrates that MMP7 plays an essential role in chondrosarcoma cell proliferation, migration, and anoikis resistance. We also found that MMP7 is highly expressed in chondrosarcomas. Our in vitro and in vivo investigations show that melatonin strongly inhibits chondrosarcoma cell proliferation, migration, and anoikis resistance by directly suppressing MMP7 expression. Melatonin reduced MMP7 synthesis by promoting levels of miR-520f-3p expression, which were downregulated in human chondrosarcoma tissue samples. Pharmacological inhibition of miR-520f-3p markedly reversed the effects of melatonin upon chondrosarcoma proliferation and metastasis. Thus, our study suggests that melatonin has therapeutic potential for reducing the tumorigenesis and metastatic potential of chondrosarcoma via the miR-520f-3p/MMP7 axis.

Posterior-Stabilized Antibiotic Cement Articulating Spacer With Endoskeleton-Reinforced Cam Reduces Rate of Post-Cam Mechanical Complications in Prosthetic Knee Infection: A Preliminary Study.

BACKGROUND: Posterior-stabilized antibiotic cement articulating spacers (PS spacers) reduce spacer mechanical complications in prosthetic knee infections (PKIs); however, joint dislocation after femoral cam fracture has been reported. We hypothesized that the rate of post-cam mechanical complications is lower in PS spacers with an endoskeleton-reinforced cam. METHOD: A retrospective study of PKIs using PS spacers with or without a Kirschner wire-reinforced cam (K-PS or nK-PS spacers, respectively) was conducted between 2015 and 2019. The rates of post-cam mechanical complications and reoperation, as well as risk factors for post or cam failure, were analyzed. RESULTS: The cohort included 118 nK-PS and 49 K-PS spacers. All patients were followed up for 2 years. The rate of joint subluxation/dislocation after femoral cam fracture was lower in K-PS (0%) than in nK-PS spacers (17.8%; P = .002). The reoperation rate for spacer mechanical complications was lower in K-PS (0%) than in nK-PS spacers (11.9%; P = .008). The identified risk factors for femoral cam fractures were body mass index ≥25 kg/m2, femoral spacer size ≤2, and surgical volume ≤12 resection arthroplasties per year. CONCLUSION: This preliminary study highlights that K-PS spacers have a lower rate of post-cam mechanical complications than nK-PS spacers. We recommend the use of PS spacers with endoskeleton-reinforced cam when treating PKIs performed by surgeons with lower surgical volumes, especially in patients with higher body mass index and smaller femoral spacer sizes.

IL-17 Facilitates VCAM-1 Production and Monocyte Adhesion in Osteoarthritis Synovial Fibroblasts by Suppressing miR-5701 Synthesis.

Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our analysis of synovial tissue samples retrieved from the Gene Expression Omnibus (GEO) dataset exhibited higher monocyte marker (CD11b) and vascular cell adhesion molecule 1 (VCAM-1) levels in OA samples than in normal, healthy samples. The stimulation of human OA synovial fibroblasts (OASFs) with IL-17 increased VCAM-1 production and subsequently enhanced monocyte adhesion. IL-17 affected VCAM-1-dependent monocyte adhesion by reducing miR-5701 expression through the protein kinase C (PKC)-α and c-Jun N-terminal kinase (JNK) signaling cascades. Our findings improve our understanding about the effect of IL-17 on OA progression and, in particular, VCAM-1 production and monocyte adhesion, which may help with the design of more effective OA treatments.

DPP4 reduces proinflammatory cytokine production in human rheumatoid arthritis synovial fibroblasts.

Rheumatoid arthritis (RA) is an autoimmune disorder that is characterized by increasing levels of proinflammatory cytokines. The ubiquitous enzyme dipeptidyl peptidase-4 (DPP4, also known as CD26) regulates different immune disorders, although the effects of DPP4 in RA are uncertain. Here, we found lower levels of DPP4 in RA synovial tissues compared with normal tissues. DPP4 levels were also lower in a rat collagen-induced arthritis model than in control (healthy) rats. Overexpression of DPP4 or exogenous treatment of RA synovial fibroblasts with DPP4 reduced levels of proinflammatory interleukin (IL)-1ß, IL-6, and IL-13, and increased anti-inflammatory IL-10 synthesis, while DPP4 inhibitors sitagliptin and vildagliptin increased proinflammatory cytokine production, indicating an enhanced risk of RA development. The evidence suggests that increasing DPP4 expression is a novel strategy for RA disease.

PM2.5 facilitates IL-6 production in human osteoarthritis synovial fibroblasts via ASK1 activation.

Osteoarthritis (OA) is a progressive degenerative joint disorder characterized by synovial inflammation. Interleukin-6 (IL-6) is a key proinflammatory cytokine in OA progression. Particulate matter 2.5 (PM2.5) exposure increases the risk of different diseases, including OA. Up until now, no studies have described any association between PM2.5 and IL-6 expression in human OA synovial fibroblasts (OASFs). Here, our data show that PM2.5 concentration- and time-dependently promoted IL-6 synthesis in human OASFs. We also found that reactive oxygen species (ROS) generation potentiated the effects of PM2.5 on IL-6 production. ASK1, ERK, p38, and JNK inhibitors reduced PM2.5-induced increases of IL-6 expression. Treatment of OASFs with PM2.5 promoted phosphorylation of these signaling cascades. We also found that PM2.5 enhanced c-Jun phosphorylation and its translocation into the nucleus. Thus, PM2.5 increases IL-6 production in human OASFs via the ROS, ASK1, ERK, p38, JNK, and AP-1 signaling pathways. Our evidence links PM2.5 with OA progression.

Cruciate-Retaining vs Posterior-Stabilized Antibiotic Cement Articulating Spacers for Two-Stage Revision of Prosthetic Knee Infection: A Retrospective Cohort Study.

BACKGROUND: Antibiotic cement articulating spacers are recommended during 2-stage revision for prosthetic knee infection because of increased range of motion (ROM) and improved function; however, spacer mechanical complications have been reported. We aimed to determine the association between different constraints of articulating spacers and the rate of complications and infection eradication, functional outcomes, and ROM. METHODS: A retrospective study of prosthetic knee infection using cruciate-retaining (CR) or posterior-stabilized (PS) spacers was conducted between 2011 and 2018. The rate of spacer mechanical complications, infection eradication after reimplantation and reoperation, Hospital of Special Surgery (HSS) knee score, and ROM during the interim stage were analyzed. All patients were regularly followed up for 2 years. RESULTS: One hundred forty-one patients were included, with 66 CR and 75 PS spacers. Overall mechanical complication rate was lower in PS (9.3%) than in CR spacers (45.5%) (P < .001), especially in joint dislocation (1.3% vs 30.3%, respectively, P < .001). Overall reoperation rate was lower in PS (16.0%) than in CR spacers (36.4%) (P < .001), especially for mechanical complications (1.3% vs 24.2%, respectively, P < .001). HSS knee score was higher in PS (72.3) than in CR spacers (63.8) (P < .001). ROM was greater in PS (90.3°) than in CR spacers (80.6°) (P = .005), especially at maximum flexion (102.4° vs 89.6°, respectively, P = .003). Infection eradication was comparable between the spacers. CONCLUSION: Both spacers can control infection; however, PS spacers had a lower rate of mechanical complications and reoperation, better HSS knee scores, and greater ROM than CR spacers.

CCL4 Stimulates Cell Migration in Human Osteosarcoma via the mir-3927-3p/Integrin αvß3 Axis.

Osteosarcoma is the most common type of primary malignant bone cancer, and it is associated with high rates of pulmonary metastasis. Integrin αvß3 is critical for osteosarcoma cell migratory and invasive abilities. Chemokine (C-C motif) ligand 4 (CCL4) has diverse effects on different cancer cells through its interaction with its specific receptor, C-C chemokine receptor type 5 (CCR5). Analysis of mRNA expression in human osteosarcoma tissue identified upregulated levels of CCL4, integrin αv and ß3 expression. Similarly, an analysis of records from the Gene Expression Omnibus (GEO) dataset showed that CCL4 was upregulated in human osteosarcoma tissue. Importantly, the expression of both CCL4 and integrin αvß3 correlated positively with osteosarcoma clinical stages and lung metastasis. Analysis of osteosarcoma cell lines identified that CCL4 promotes integrin αvß3 expression and cell migration by activating the focal adhesion kinase (FAK), protein kinase B (AKT), and hypoxia inducible factor 1 subunit alpha (HIF-1α) signaling pathways, which can downregulate microRNA-3927-3p expression. Pharmacological inhibition of CCR5 by maraviroc (MVC) prevented increases in integrin αvß3 expression and cell migration. This study is the first to implicate CCL4 as a potential target in the treatment of metastatic osteosarcoma.

Visfatin Promotes the Metastatic Potential of Chondrosarcoma Cells by Stimulating AP-1-Dependent MMP-2 Production in the MAPK Pathway.

Chondrosarcoma is a malignant bone tumor that is characterized by high metastatic potential and marked resistance to radiation and chemotherapy. The knowledge that adipokines facilitate the initiation, progression, metastasis, and treatment resistance of various tumors has driven several in vitro and in vivo investigations into the effects of adipokines resistin, leptin, and adiponectin upon the development and progression of chondrosarcomas. Another adipokine, visfatin, is known to regulate tumor progression and metastasis, although how this molecule may affect chondrosarcoma metastasis is unclear. Here, we found that visfatin facilitated cellular migration via matrix metalloproteinase-2 (MMP-2) production in human chondrosarcoma cells and overexpression of visfatin enhanced lung metastasis in a mouse model of chondrosarcoma. Visfatin-induced stimulation of MMP-2 synthesis and activation of the AP-1 transcription factor facilitated chondrosarcoma cell migration via the ERK, p38, and JNK signaling pathways. This evidence suggests that visfatin is worth targeting in the treatment of metastatic chondrosarcoma.

S1P promotes IL-6 expression in osteoblasts through the PI3K, MEK/ERK and NF-κB signaling pathways.

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks joint tissue. Interleukin (IL)-6 is a key proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we examined the effects of S1P on IL-6 expression in osteoblasts. Our results and records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-6 in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P increased mRNA and protein expression of IL-6. PI3K, MEK, ERK and NF-κB inhibitors and their small interfering RNAs (siRNAs) reduced S1P-promoted IL-6 expression. S1P also facilitated PI3K, MEK/ERK and NF-κB signaling cascades. Our results indicate that S1P promotes the expression of IL-6 in osteoblasts via the PI3K, MEK/ERK and NF-κB signaling pathways.

S1P facilitates IL-1ß production in osteoblasts via the JAK and STAT3 signaling pathways.

Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease, in which the immune system attacks synovial joint tissues. Interleukin (IL)-1ß is a critical proinflammatory cytokine in RA progression. Sphingosine-1-phosphate (S1P), a platelet-derived lysophospholipid mediator, reportedly regulates osteoimmunology. Here, we investigated how S1P mediates IL-1ß expression in osteoblasts. Our analysis of records from the Gene Expression Omnibus (GEO) database demonstrate higher levels of IL-1ß in patients with RA compared with those with osteoarthritis. Stimulation of osteoblasts with S1P concentration dependently increased mRNA and protein expression of IL-1ß. Elevations in IL-1ß mRNA expression induced by S1P were reduced by the small interfering RNA (siRNA) against the S1P1 receptor. S1P also augmented JAK and STAT3 molecular cascades. We also found that JAK and STAT3 inhibitors and their siRNAs antagonized S1P-promoted IL-1ß expression. Our results indicate that S1P promotes the expression of IL-1ß in osteoblasts via the S1P1 receptor and the JAK and STAT3 signaling pathways.

CXCL13/CXCR5 Interaction Facilitates VCAM-1-Dependent Migration in Human Osteosarcoma.

Osteosarcoma is the most common primary tumor of the skeletal system and is well-known to have an aggressive clinical outcome and high metastatic potential. The chemokine (C-X-C motif) ligand 13 (CXCL13) plays a vital role in the development of several cancers. However, the effect of CXCL13 in the motility of osteosarcoma cells remains uncertain. Here, we found that CXCL13 increases the migration and invasion potential of three osteosarcoma cell lines. In addition, CXCL13 expression was upregulated in migration-prone MG-63 cells. Vascular cell adhesion molecule 1 (VCAM-1) siRNA and antibody demonstrated that CXCL13 promotes migration via increasing VCAM-1 production. We also show that CXCR5 receptor controls CXCL13-mediated VCAM-1 expression and cell migration. Our study identified that CXCL13/CXCR5 axis facilitate VCAM-1 production and cell migration in human osteosarcoma via the phospholipase C beta (PLCß), protein kinase C α (PKCα), c-Src, and nuclear factor-κB (NF-κB) signaling pathways. CXCL13 and CXCR5 appear to be a novel therapeutic target in metastatic osteosarcoma.

CCN2 promotes drug resistance in osteosarcoma by enhancing ABCG2 expression.

In recent years, osteosarcoma survival rates have failed to improve significantly with conventional treatment modalities because of the development of chemotherapeutic resistance. The human breast cancer resistance protein/ATP binding cassette subfamily G member 2 (BCRP/ABCG2), a member of the ATP-binding cassette family, uses ATP hydrolysis to expel xenobiotics and chemotherapeutics from cells. CCN family member 2 (CCN2) is a secreted protein that modulates the biological function of cancer cells, enhanced ABCG2 protein expression and activation in this study via the α6ß1 integrin receptor and increased osteosarcoma cell viability. CCN2 treatment downregulated miR-519d expression, which promoted ABCG2 expression. In a mouse xenograft model, knockdown of CCN2 expression increased the therapeutic effect of doxorubicin, which was reversed by ABCG2 overexpression. Our data show that CCN2 increases ABCG2 expression and promotes drug resistance through the α6ß1 integrin receptor, whereas CCN2 downregulates miR-519d. CCN2 inhibition may represent a new therapeutic concept in osteosarcoma.

Amphiregulin Promotes Vascular Endothelial Growth Factor-C Expression and Lymphangiogenesis through STAT3 Activation in Human Chondrosarcoma Cells.

BACKGROUND/AIMS: Chondrosarcoma is the second most common primary malignancy of bone, characterized by a high metastatic potential. Increasing clinical data highlight the important role played by lymphangiogenesis in cancer metastasis. Amphiregulin (AR) has been implicated in tumor metastasis and lymphangiogenesis, but its association with vascular endothelial growth factor-C (VEGF-C) expression and lymphangiogenesis in chondrosarcoma is unclear. METHODS: We used qPCR, ELISA and Western blotting to detect AR-induced VEGF-C expression in chondrosarcoma cells. Lymphangiogenesis was investigated by lymphatic endothelial cells (LECs) migration and tube formation. An in vivo experiment examined AR expression in tumor-associated lymphangiogenesis. RESULTS: In this study, we found that both AR and VEGF-C expression correlated with tumor stage and were significantly higher than levels found in normal cartilage. Exogenous AR promoted VEGF-C expression in chondrosarcoma cells in a time- and dose-dependent manner and subsequently increased migration and tube formation of LECs. AR also increased VEGF-C expression and lymphangiogenesis through the Src/MEK/ERK/STAT3 signaling pathway. However, it is unclear as to how an EGFR ligand (AR) induces activation of the Src kinase. Knockdown of AR decreased VEGF-C expression in chondrosarcoma cells. Similarly, lymphangiogenesis was abolished in AR knockdown cells in an in vivo model of chondrosarcoma. CONCLUSION: These results indicate that AR occurs through the Src/MEK/ERK/STAT-3 pathway, activating VEGF-C expression and contributing to lymphangiogenesis in human chondrosarcoma. Thus, AR could be a therapeutic target in metastasis and lymphangiogenesis of chondrosarcoma.

Resistin Enhances Monocyte Chemoattractant Protein-1 Production in Human Synovial Fibroblasts and Facilitates Monocyte Migration.

BACKGROUND/AIMS: The adipocyte-secreting adipokine, resistin, may play a critical role in the modulation of inflammatory diseases. Migration and infiltration of mononuclear cells into inflammatory sites are critical events during the development of osteoarthritis (OA). Monocyte chemoattractant protein-1 (MCP-1), also known as chemokine ligand 2 (CCL2), plays a critical role in the regulation of monocyte migration and infiltration. In this study, we show how resistin promotes MCP-1 expression in OA synovial fibroblasts and monocyte migration. METHODS: We used qPCR to detect MCP-1 and miRNA expression. THP-1 migration was investigated by Transwell assay. The Western blotting was used to examine the resistinmediated signaling pathways. RESULTS: Resistin activated the phosphatidylinositol-3-kinase (PI3K), Akt and mammalian target of rapamycin (mTOR) signaling pathways, while PI3K, Akt and mTOR inhibitors or small interfering RNAs diminished resistin-induced MCP-1 expression and monocyte migration. We also demonstrate that resistin stimulates MCP-1mediated monocyte migration by suppressing microRNA (miR)-33a and miR-33b via the PI3K, Akt and mTOR signaling pathways. CONCLUSION: These results provide new insights into the mechanisms of resistin action that may have therapeutic implications for patients with OA.

CCN3 Facilitates Runx2 and Osterix Expression by Inhibiting miR-608 through PI3K/Akt Signaling in Osteoblasts.

CCN3, otherwise known as the nephroblastoma overexpressed (NOV) protein, is a cysteine-rich protein that belongs to the CCN family and regulates several cellular functions. Osteoblasts are major bone-forming cells that undergo proliferation, mineralization, renewal, and repair during the bone formation process. We have previously reported that CCN3 increases bone morphogenetic protein 4 (BMP-4) production and bone mineralization in osteoblasts, although the role of CCN3 remains unclear with regard to osteogenic transcription factors (runt-related transcription factor 2 (Runx2) and osterix). Here, we used alizarin red-S and alkaline phosphatase staining to show that CCN3 enhances osteoblast differentiation. Stimulation of osteoblasts with CCN3 increases expression of osteogenic factors such as BMPs, Runx2, and osterix. Moreover, we found that the inhibition of miR-608 expression is involved in the effects of CCN3 and that incubation of osteoblasts with CCN3 promotes focal adhesion kinase (FAK) and Akt phosphorylation. Our results indicate that CCN3 promotes the expression of Runx2 and osterix in osteoblasts by inhibiting miR-608 expression via the FAK and Akt signaling pathways.

Glucose enhances aggrecan expression in chondrocytes via the PKCα/p38-miR141-3p signaling pathway.

Aggrecan is a high molecular weight proteoglycan that plays a critical role in cartilage structure and the function of joints, providing intervertebral disc and cartilage with the ability to resist compressive loads. Aggrecan degradation in articular cartilage is a significant event in early-stage osteoarthritis (OA). Currently, no effective treatment exists for OA other than pain relief. Dextrose (D-glucose) prolotherapy has shown promising activity in the treatment of different musculoskeletal disorders, including OA. However, little is known about the molecular mechanism of the glucose effect in OA and on the regulation of chondrogenesis. We show for the first time that glucose upregulates aggrecan expression and subsequent chondrogenesis in ATDC5 cells. Moreover, we found that glucose-induced aggrecan expression is mediated through the protein kinase Cα (PKCα)- and p38-dependent pathway. As demonstrated by microRNA (miR) and luciferase analyses, the glucose-induced PKCα/p38 signaling axis is responsible for downregulating miR141-3p which targets to the 3'untranslated region of aggrecan. In summary, we show that glucose enhances chondrogenesis by upregulating aggrecan expression via the PKCα-p38-miR141-3p signaling pathway. This result provides new insights into the mechanism of glucose on chondrogenesis.