Olfactory-ensheathing cells (OECs) are known for their role in neuronal regeneration and potential to promote tissue repair. Adipose-derived stem cells (ADSCs), characterized by mesenchymal stem cell (MSC) traits, display a fibroblast-like morphology and express MSC surface markers, making them suitable for regenerative therapies for osteoarthritis (OA). In this study, OECs and ADSCs were derived from tissues and characterized for their morphology, surface marker expression, and differentiation capabilities. Collagenase-induced OA was created in 10-week-old C57BL/6 mice, followed by intra-articular injections of ADSCs (1 × 105), OECs (1 × 105), or a higher dose of OECs (5 × 105). Therapeutic efficacy was evaluated using rotarod performance tests, MRI, histology, and immunohistochemistry. Both cell types exhibited typical MSC characteristics and successfully differentiated into adipocytes, osteoblasts, and chondrocytes, confirmed by gene expression and staining. Transplantation significantly improved rotarod performance and preserved cartilage integrity, as seen in MRI and histology, with reduced cartilage destruction and increased chondrocytes. Immunohistochemistry showed elevated type II collagen and aggrecan in treated joints, indicating hyaline cartilage formation, and reduced MMP13 and IL-1β expression, suggesting decreased inflammation and catabolic activity. These findings highlight the regenerative potential of OECs and ADSCs in treating OA by preserving cartilage, promoting chondrocyte proliferation, and reducing inflammation. Further research is needed to optimize delivery methods and evaluate long-term clinical outcomes.

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OBJECTIVE: Matrix metalloproteinase 13 (MMP13) has been reported to be involved in tumor development and progression, including of colorectal cancer (CRC). This study aimed at evaluating whether the MMP13 rs2252070 gene polymorphism is associated with clinicopathological factors and its influence on long-term survival in Swedish patients with CRC.
METHODS: A total of 723 patients with CRC were genotyped using TaqMan single nucleotide polymorphism assays based on polymerase chain reaction.
RESULTS: Assessing clinicopathological factors, we demonstrated that having the G/G genotype for MMP13 rs2252070 was significantly associated with poor differentiation, higher serum level of carcinoembryonic antigen and higher lymph node status. Moreover, the presence of a G allele was significantly related to larger tumor size in rectal cancer but had a significantly protective role against mucinous cancer, perineural invasion and lymphovascular invasion. Kaplan-Meier analysis showed no difference between genotypes regarding cancer-specific survival.
CONCLUSIONS: Our findings highlight the potential of MMP13 rs2252070 polymorphism as a useful predictor of poor differentiation, serum level of carcinoembryonic antigen, lymph node status, tumor size, mucinous cancer, perineural invasion and lymphovascular invasion in patients with CRC.

Ca2+ permeation through TRPV4 in fibroblasts is associated with pathological matrix degradation. In human gingival fibroblasts, IL-1β binding to its signaling receptor (IL-1R1) induces activation of extracellular regulated kinase (ERK) and MMP1 expression, processes that require Ca2+ flux across the plasma membrane. It is not known how IL-1R1, which does not conduct Ca2+, generates Ca2+ signals in response to IL-1. We examined whether TRPV4 mediates the Ca2+ fluxes required for ERK signaling in IL-1 stimulated gingival fibroblasts. TRPV4 was immunostained in fibroblasts of human gingival connective tissue and in focal adhesions of cultured mouse gingival fibroblasts. Human gingival fibroblasts treated with IL-1β showed no change of TRPV4 expression but there was increased MMP1 expression. In mouse, gingival fibroblasts expressing TRPV4, IL-1 strongly increased [Ca2+]i. Pre-incubation of cells with IL-1 Receptor Antagonist blocked Ca2+ entry induced by IL-1 or the TRPV4 agonist GSK101. Knockout of TRPV4 or expression of a non-Ca2+-conducting TRPV4 pore-mutant or pre-incubation with the TRPV4 inhibitor RN1734, blocked IL-1-induced Ca2+ transients and expression of the mouse interstitial collagenase, MMP13. Treatment of mouse gingival fibroblasts with GSK101 phenocopied Ca2+ and ERK responses induced by IL-1; these responses were absent in TRPV4-null cells or cells expressing a non-conducting TRPV4 pore-mutant. Immunostained IL-1R1 localized with TRPV4 in adhesions within cell extensions. While TRPV4 immunoprecipitates analyzed by mass spectrometry showed no association with IL-1R1, TRPV4 associated with Src-related proteins and Src co-immunoprecipitated with TRPV4. Src inhibition reduced IL-1-induced Ca2+ responses. The functional linkage of TRPV4 with IL-1R1 expands its repertoire of innate immune signaling processes by mediating IL-1-driven Ca2+ responses that drive matrix remodeling in fibroblasts. Thus, inhibiting TRPV4 activity may provide a new pharmacological approach for blunting matrix degradation in inflammatory diseases.

UNASSIGNED: The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.
UNASSIGNED: We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively.
UNASSIGNED: bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1+MMP13high in GC and bsPD-L1+(MMP3 and MMP13)increased in NSCLC were associated with poor prognosis, whereas bsPD-L1+MMP13low in GC and bsPD-L1+(MMP3 or MMP13)decreased in NSCLC were associated with favorable prognosis.
UNASSIGNED: Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

UNASSIGNED: This study seeks to identify potential clinical biomarkers for osteoarthritis (OA) using bioinformatics and investigate OA mechanisms through cellular assays.
UNASSIGNED: Differentially Expressed Genes (DEGs) from GSE52042 (four OA samples, four control samples) were screened and analyzed with protein-protein interaction (PPI) analysis. Overlapping genes in GSE52042 and GSE206848 (seven OA samples, and seven control samples) were identified and evaluated using Gene Set Enrichment Analysis (GSEA) and clinical diagnostic value analysis to determine the hub gene. Finally, whether and how the hub gene impacts LPS-induced OA progression was explored by in vitro experiments, including Western blotting (WB), co-immunoprecipitation (Co-IP), flow cytometry, etc.
UNASSIGNED: Bioinformatics analysis of DEGs (142 up-regulated and 171 down-regulated) in GSE52042 identified two overlapping genes (U2AF2, TPX2) that exhibit significant clinical diagnostic value. These genes are up-regulated in OA samples from both GSE52042 and GSE206848 datasets. Notably, TPX2, which AUC = 0.873 was identified as the hub gene. In vitro experiments have demonstrated that silencing TPX2 can alleviate damage to chondrocytes induced by lipopolysaccharide (LPS). Furthermore, there is a protein interaction between TPX2 and MMP13 in OA. Excessive MMP13 can attenuate the effects of TPX2 knockdown on LPS-induced changes in OA protein expression, cell growth, and apoptosis.
UNASSIGNED: In conclusion, our findings shed light on the molecular mechanisms of OA and suggested TPX2 as a potential therapeutic target. TPX2 could promote the progression of LPS-induced OA by up-regulating the expression of MMP13, which provides some implications for clinical research.

Targeted drug delivery and the reduction of off-target effects are crucial for the promising clinical application of nucleic acid drugs. To address this challenge, a new approach for treating osteoarthritis (OA) that accurately delivers antisense oligonucleotides (ASO) targeting matrix metalloproteinase-13 (ASO-MMP13) to chondrocytes, is developed. Small extracellular vesicles (exos) are ligated with chondrocyte affinity peptide (CAP) using Sortase A and subsequently incubated with cholesterol-modified ASO-MMP13 to construct a chondrocyte-targeted drug delivery exo (CAP-exoASO). Compared with exos without CAP (ExoASO), CAP-exoASOs attenuate IL-1β-induced chondrocyte damage and prolong the retention time of ASO-MMP13 in the joint without distribution in major organs following intra-articular injection. Notably, CAP-exoASOs decrease MMP13 expression (P < 0.001) and upregulate COL2A1 expression (P = 0.006), resulting in reorganization of the cartilage matrix and alleviation of progression in the OA model. Furthermore, the Osteoarthritis Research Society International (OARSI) score of articular cartilage tissues treated with CAP-exoASO is comparable with that of healthy rats (P = 0.148). A mechanistic study demonstrates that CAP-exoASO may reduce inflammation by suppressing the IL-17 and TNF signaling pathways. Based on the targeted delivery effect, CAP-exoASOs successfully accomplish cartilage repair and have considerable potential for development as a promising therapeutic modality for satisfactory OA therapy.

The histone variant, macroH2A (mH2A) influences gene expression through epigenetic regulation. Tumor suppressive function of mH2A isoforms has been reported in various cancer types, but few studies have investigated the functional role of mH2A2 in breast cancer pathophysiology. This study aimed to determine the significance of mH2A2 in breast cancer development and progression by exploring its downstream regulatory mechanisms. Knockdown of mH2A2 facilitated the migration and invasion of breast cancer cells, whereas its overexpression exhibited the opposite effect. In vivo experiments revealed that augmenting mH2A2 expression reduced tumor growth and lung metastasis. Microarray analysis showed that TM4SF1 emerged as a likely target linked to mH2A2 owing to its significant suppression in breast cancer cell lines where mH2A2 was overexpressed among the genes that exhibited over twofold upregulation upon mH2A2 knockdown. Suppressing TM4SF1 reduced the migration, invasion, tumor growth, and metastasis of breast cancer cells in vitro and in vivo. TM4SF1 depletion reversed the increased aggressiveness triggered by mH2A2 knockdown, suggesting a close interplay between mH2A2 and TM4SF1. Our findings also highlight the role of the mH2A2/TM4SF1 axis in activating the AKT/NF-κB pathway. Consequently, activated NF-κB signaling leads to increased expression and secretion of MMP13, a potent promoter of metastasis. In summary, we propose that the orchestrated regulation of the mH2A2/TM4SF1 axis in conjunction with the AKT/NF-κB pathway and the subsequent elevation in MMP13 expression constitute pivotal factors governing the malignancy of breast cancer.

BACKGROUND: Breast cancer (BC) patients tend to suffer from distant metastasis, especially bone metastasis.
METHODS: All the analysis based on open-accessed data was performed in R software, dependent on multiple algorithms and packages. The RNA levels of specific genes were detected using quantitative Real-time PCR as a method of detecting the RNA levels. To assess the ability of BC cells to proliferate, we utilized the CCK8 test, colony formation, and the 5-Ethynyl-20-deoxyuridine assay. BC cells were evaluated for invasion and migration by using Transwell assays and wound healing assays.
RESULTS: In our study, we identified the molecules involved in BC bone metastasis based on the data from multiple BC cohorts. Then, we comprehensively investigated the effect pattern and underlying biological role of these molecules. We found that in the identified molecules, the EMP1, ACKR3, ITGA10, MMP13, COL11A1, and THY1 were significantly correlated with patient prognosis and mainly expressed in CAFs. Therefore, we explored the CAFs in the BC microenvironment. Results showed that CAFs could activate multiple carcinogenic pathways and most of these pathways play an important role in cancer metastasis. Meanwhile, we noticed the interaction between CAFs and malignant, endothelial, and M2 macrophage cells. Moreover, we found that CAFs could induce the remodeling of the BC microenvironment and promote the malignant behavior of BC cells. Then, we identified MMP13 for further analysis. It was found that MMP13 can enhance the malignant phenotype of BC cells. Meanwhile, biological enrichment and immune infiltration analysis were conducted to present the effect pattern of MMP13 in BC.
CONCLUSIONS: Our result can improve the understanding of researchers on the underlying mechanisms of BC bone metastasis.

Renal fibrosis is the most common manifestation of end-stage renal disease (ESRD), including diabetic kidney disease (DKD), but there is no effective treatment in renal fibrosis. Natural products are a rich source of clinical drug research and have been used in the clinical research of various diseases. In this study, we searched for traditional Chinese medicine monomers that attenuate fibrosis and assessed their effect on the fibrosis marker connective tissue growth factor (CTGF) in cells which we found ecliptasaponin A. Subsequently, we evaluated the effect of ecliptasaponin A on renal fibrosis in the classic renal fibrosis unilateral ureteral obstruction (UUO) mouse model and found that ecliptasaponin A could reduce the renal collagen fiber deposition and renal extracellular matrix (ECM) protein expression in UUO mice. In vitro, ecliptasaponin A can inhibit ECM protein expression in human kidney-2 (HK-2) cells induced by transforming growth factor-beta1 (TGFβ1). To further clarify the mechanism of ecliptasaponin A in attenuating renal fibrosis, we performed transcriptome sequencing of HK-2 cells treated with TGFβ1 and ecliptasaponin A. The functions and pathways were mainly enriched in the extracellular matrix and TGFβ signalling pathway. Matrix metalloproteinase 10 (MMP10) and matrix metalloproteinase 13 (MMP13) are the main differentially expressed genes in extracellular matrix regulation. Then, we measured MMP10 and MMP13 in the cells and found that ecliptasaponin A had a significant inhibitory effect on MMP13 expression but not on MMP10 expression. Furthermore, we overexpressed MMP13 in HK-2 cells treated with TGFβ1 and found that MMP13 promoted HK-2 cell injury. Our findings suggest that ecliptasaponin A can attenuate renal fibrosis, which may provide a new method for treating renal fibrosis clinically.