Experimental cell research · 2025
MSX2 serves as a chondroprotective factor in osteoarthritis: insights from expression analysis and functional validation studies.
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Wu Shuai, Li Bin, Tao Fulin, Song Wenhao, Zhang Guoming, Wang Rui, Tian Zhoubin
Аннотация
OBJECTIVE: Despite the high prevalence of osteoarthritis (OA), molecular mechanisms underlying cartilage destruction remain incompletely understood. This study investigated the expression pattern and functional role of muscle segment homeobox 2 (MSX2) in osteoarthritis pathogenesis.
METHODS: Differential gene expression analysis was performed using three independent Gene Expression Omnibus (GEO) datasets (GSE55457, GSE12021, and GSE114007) to examine MSX2 expression in osteoarthritic versus normal cartilage. Expression patterns were validated in primary chondrocytes from human osteoarthritis patients and mouse osteoarthritis models using Western blot and quantitative reverse transcription polymerase chain reaction (RT-PCR). Functional studies employed both loss-of-function and gain-of-function approaches through intra-articular injection of adeno-associated virus expressing MSX2-specific short hairpin ribonucleic acid (shRNA) or MSX2 overexpression constructs. Cartilage morphology, proteoglycan content, chondrocyte apoptosis, matrix markers, and inflammatory responses were assessed through histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) staining.
RESULTS: MSX2 was consistently downregulated in osteoarthritic samples across all datasets, with validation confirming reduced MSX2 protein and messenger ribonucleic acid (mRNA) levels in both human patients and mouse models (p < 0.05). MSX2 knockdown significantly exacerbated cartilage degeneration, increased chondrocyte apoptosis, and disrupted matrix homeostasis by reducing anabolic markers type II collagen (COL2) and aggrecan (ACAN) while upregulating matrix metalloproteinase 13 (MMP13). Additionally, MSX2 knockdown enhanced inflammatory responses, evidenced by increased macrophage infiltration and tumor necrosis factor-alpha (TNFα) expression. Conversely, MSX2 overexpression demonstrated chondroprotective effects with improved cartilage morphology and reduced apoptosis.
CONCLUSION: MSX2 serves as a critical chondroprotective factor maintaining cartilage homeostasis. Its downregulation contributes to osteoarthritis pathogenesis through disruption of matrix homeostasis, promotion of chondrocyte apoptosis, and enhancement of inflammatory responses. These findings identify MSX2 as a potential therapeutic target for osteoarthritis treatment.
METHODS: Differential gene expression analysis was performed using three independent Gene Expression Omnibus (GEO) datasets (GSE55457, GSE12021, and GSE114007) to examine MSX2 expression in osteoarthritic versus normal cartilage. Expression patterns were validated in primary chondrocytes from human osteoarthritis patients and mouse osteoarthritis models using Western blot and quantitative reverse transcription polymerase chain reaction (RT-PCR). Functional studies employed both loss-of-function and gain-of-function approaches through intra-articular injection of adeno-associated virus expressing MSX2-specific short hairpin ribonucleic acid (shRNA) or MSX2 overexpression constructs. Cartilage morphology, proteoglycan content, chondrocyte apoptosis, matrix markers, and inflammatory responses were assessed through histological analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) staining.
RESULTS: MSX2 was consistently downregulated in osteoarthritic samples across all datasets, with validation confirming reduced MSX2 protein and messenger ribonucleic acid (mRNA) levels in both human patients and mouse models (p < 0.05). MSX2 knockdown significantly exacerbated cartilage degeneration, increased chondrocyte apoptosis, and disrupted matrix homeostasis by reducing anabolic markers type II collagen (COL2) and aggrecan (ACAN) while upregulating matrix metalloproteinase 13 (MMP13). Additionally, MSX2 knockdown enhanced inflammatory responses, evidenced by increased macrophage infiltration and tumor necrosis factor-alpha (TNFα) expression. Conversely, MSX2 overexpression demonstrated chondroprotective effects with improved cartilage morphology and reduced apoptosis.
CONCLUSION: MSX2 serves as a critical chondroprotective factor maintaining cartilage homeostasis. Its downregulation contributes to osteoarthritis pathogenesis through disruption of matrix homeostasis, promotion of chondrocyte apoptosis, and enhancement of inflammatory responses. These findings identify MSX2 as a potential therapeutic target for osteoarthritis treatment.