image: (A) Primary chondrocyte cells were subjected to treatment with different melatonin concentrations, spanning from 0.1 to 100 μM, for 72 h. CCK8 assay revealed that 0.1, 10, and 50 μM melatonin treatments had no impact on cell viability, and the viability of cells notably decreased with the application of 100 μM melatonin. (B) The recorded cell morphology of each group was representative. Scale bars, 200 μm. (C) Ki67 immunostaining of chondrocytes. Scale bars, 200 μm. (D–F) Immunofluorescent assessments were conducted on chondrogenic markers SOX9, COL II, and ACAN. Scale bars, 200 μm. (G) Measurement of cells expressing Ki67 and SOX9 and chondrocytes labeled with COL II and ACAN. (H) Real-time quantitative PCR was employed to analyze the expression levels of Sox9, Col2a1, and Acan mRNA. Statistical significance was assessed through One-way ANOVA followed by Tukey's multiple comparisons test. The results are presented as mean ± standard deviation, with ∗P < 0.05, ∗∗P < 0.01, ∗∗∗P < 0.001, and ∗∗∗∗P < 0.0001 indicating statistical significance, while “ns” denotes no statistical significance. SOX9, SRY-box transcription factor 9; COL II, collagen type II; ACAN, aggrecan; SLC26A2, Solute carrier family 26 member 2; CTR, cre-negative control.
Credit: Genes & Diseases
Solute carrier family 26 member 2 (SLC26A2) is an SO42− transporter, facilitating the uptake of inorganic sulfate into cells. Mutations in SLC26A2 lead to chondrodysplasia, a rare genetic disorder characterized by abnormal cartilage development that affects bone growth. Unfortunately, the current challenge lies in the absence of effective pharmaceutical interventions for SLC26A2-associated chondrodysplasias.
This research, published in the Genes & Diseases journal by a team from the Fourth Military Medical University, Xi’an Jiaotong University, and Northwestern University, Xi’an, Shaanxi, investigate the therapeutic effects of an indoleamine hormone, melatonin, on SLC26A2-deficient chondrodysplasias.
In the in vitro studies, the researchers found that melatonin ameliorates impaired anabolism and proliferation of Slc26a2-deficient chondrocytes and attenuates activation of unfolded protein response (UPR) induced by Slc26a2 deficiency. Additionally, melatonin also suppressed cytoplasmic calcium overload and significantly inhibited cell death in Slc26a2-deficient chondrocytes.
In the in vivo studies, the research findings indicated that melatonin could effectively rescue defective formation and abnormal morphology of bone in cartilage-specific Slc26a2 knockout mice (Slc26a2 cKO), which is in line with in vitro mitigating effects. Notably, the histological analysis revealed that melatonin attenuates ER stress and cell death in growth plate cartilage of Slc26a2 cKO mice. Furthermore, melatonin significantly inhibited the expression of proapoptotic proteins, including BAX, cleaved CASP3, and CHOP, while enhancing the expression of the anti-apoptotic protein BCL2. These findings support the effectiveness of melatonin in treating SLC26A2-associated skeletal disorders, highlighting its potential as a therapeutic option.
Although these collective data provide translational insights for drug development, further studies are necessary to fully elucidate melatonin’s multifaceted roles in regulating chondrocyte’s function and cell fate. In conclusion, the researchers underscore the importance of continued research and development to harness the full therapeutic potential of melatonin for addressing SLC26A2-related skeletal conditions.
Reference
Title of the original paper: Melatonin ameliorates Slc26a2-associated chondrodysplasias by attenuating endoplasmic reticulum stress and apoptosis of chondrocytes
Journal: Genes & Diseases
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DOI: https://doi.org/10.1016/j.gendis.2024.101350
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Journal
Genes & Diseases
Article Title
Melatonin Identified as a Potential Therapeutic Agent For SLC26A2-Related Chondrodysplasias