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Differential regulation of the water channel protein aquaporins in chondrocytes of human knee articular cartilage by aging.

ABSTRACT: Knee cartilage is in an aqueous environment filled with synovial fluid consisting of water, various nutrients, and ions to maintain chondrocyte homeostasis. Aquaporins (AQPs) are water channel proteins that play an important role in water exchange in cells, and AQP1, -3, and -4 are known to be expressed predominantly in cartilage. We evaluated the changes in AQP expression in chondrocytes from human knee articular cartilage in patients of different ages and identified the key factor(s) that mediate age-induced alteration in AQP expression. The mRNA and protein expression of AQP1, -3 and -4 were significantly decreased in fibrocartilage compared to hyaline cartilage and in articular cartilage from older osteoarthritis patients compared to that from young patients. Gene and protein expression of AQP1, -3 and -4 were altered during the chondrogenic differentiation of C3H10T1/2 cells. The causative factors for age-associated decrease in AQP included H₂O₂, TNFα, and HMGB1 for AQP1, -3, and -4, respectively. In particular, the protective effect of AQP4 reduction following HMGB1 neutralization was noteworthy. The identification of other potent molecules that regulate AQP expression represents a promising therapeutic approach to suppress cartilage degeneration during aging.

SUBMITTER: Kyung BS

PROVIDER: S-EPMC8516946 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Differential regulation of the water channel protein aquaporins in chondrocytes of human knee articular cartilage by aging.

Kyung Bong Soo BS Jung Koo Whang KW Yeo Woo Jin WJ Seo Hye Kyung HK Lee Yong-Soo YS Suh Dong Won DW

Scientific reports 20211014 1

Knee cartilage is in an aqueous environment filled with synovial fluid consisting of water, various nutrients, and ions to maintain chondrocyte homeostasis. Aquaporins (AQPs) are water channel proteins that play an important role in water exchange in cells, and AQP1, -3, and -4 are known to be expressed predominantly in cartilage. We evaluated the changes in AQP expression in chondrocytes from human knee articular cartilage in patients of different ages and identified the key factor(s) that medi ...[more]

PMID: 34650163

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Project description:ObjectiveOur previous study suggested that growth arrest and DNA damage-inducible protein 45beta (GADD45beta) prolonged the survival of hypertrophic chondrocytes in the developing mouse embryo. This study was undertaken, therefore, to investigate whether GADD45beta plays a role in adult articular cartilage.MethodsGene expression profiles of cartilage from patients with late-stage osteoarthritis (OA) were compared with those from patients with early OA and normal controls in 2 separate microarray analyses. Histologic features of cartilage were graded using the Mankin scale, and GADD45beta was localized by immunohistochemistry. Human chondrocytes were transduced with small interfering RNA (siRNA)-GADD45beta or GADD45beta-FLAG. GADD45beta and COL2A1 messenger RNA (mRNA) levels were analyzed by real-time reverse transcriptase-polymerase chain reaction, and promoter activities were analyzed by transient transfection. Cell death was detected by Hoechst 33342 staining of condensed chromatin.ResultsGADD45beta was expressed at higher levels in cartilage from normal donors and patients with early OA than in cartilage from patients with late-stage OA. All chondrocyte nuclei in normal cartilage immunostained for GADD45beta. In early OA cartilage, GADD45beta was distributed variably in chondrocyte clusters, in middle and deep zone cells, and in osteophytes. In contrast, COL2A1, other collagen genes, and factors associated with skeletal development were up-regulated in late OA, compared with early OA or normal cartilage. In overexpression and knockdown experiments, GADD45beta down-regulated COL2A1 mRNA and promoter activity. NF-kappaB overexpression increased GADD45beta promoter activity, and siRNA-GADD45beta decreased cell survival per se and enhanced tumor necrosis factor alpha-induced cell death in human articular chondrocytes.ConclusionThese observations suggest that GADD45beta might play an important role in regulating chondrocyte homeostasis by modulating collagen gene expression and promoting cell survival in normal adult cartilage and in early OA.

Project description:Shenmai injection (SMI) has been widely used as a therapy to treat a number of diseases. However, its anti-osteoarthritic properties have not yet been fully investigated. In the present study, the protective effect of SMI on knee articular cartilage of anterior cruciate ligament transected rabbits and interleukin-1β (IL-1β)-stimulated human chondrocytes was investigated. For the in vivo study, knee osteoarthritis (KOA) was induced in female New Zealand white rabbits by anterior cruciate ligament transection (ACLT) in the knee of right hind limb. Rabbits either underwent sham surgery or ACLT surgery. Out of the rabbits receiving ACLT surgery, half of the rabbits received one 0.3 ml Shenmai intra-articular injection in the knee per week for four weeks, following ACLT surgery. The other rabbits received the same volume of normal saline solution. The cartilage was subsequently collected for histological evaluation. For the in vitro study, cultured human chondrocytes were treated with 10 ng/ml IL-1β in the presence or absence of 5 and 2% (v/v) SMI for 24 h. Nitric oxide (NO) and prostaglandin E2 (PGE2) levels in cell culture supernatant were assessed using a Griess reaction and ELISA respectively. The mRNA expression of cyclooxgenase-2 (COX-2), inducible nitric oxide synthase (iNOS), matrix metalloproteinase (MMP)-1, MMP-13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) in chondrocytes were detected by reverse transcription-quantitative polymerase chain reaction. The results of the current study revealed that treatment with SMI ameliorated cartilage degradation in the ACLT rabbit model, and decreased levels of NO and PGE2. Furthermore, treatment with SMI decreased levels of COX-2, iNOS, MMP-1 and MMP-13 mRNA expression and increased TIMP-1 mRNA expression in IL-1β-stimulated human chondrocytes. These results indicate that SMI suppresses inflammation and ameliorated cartilage degradation, making it a potential and promising therapeutic option to treat KOA.

Dataset Information

Differential regulation of the water channel protein aquaporins in chondrocytes of human knee articular cartilage by aging.

Publications

Differential regulation of the water channel protein aquaporins in chondrocytes of human knee articular cartilage by aging.

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