Abstract
BackgroundHypertrophy is a critical process for chondrocyte differentiation and maturation during endochondral ossification, which is responsible for the formation of long bone and postnatal longitudinal growth. Increasing evidence suggests that melatonin, an indole hormone, plays a pivotal role in chondrogenesis. However, little is known about the effects of melatonin on the terminal differentiation of chondrocytes.MethodsMesenchymal stem cell (MSC)-derived chondrocytes generated by a high-density micromass culture system were induced to undergo hypertrophic differentiation. Melatonin-mediated hypertrophic differentiation was examined by reverse transcription polymerase chain reaction analysis (RT-PCR) analysis, histological staining and immunohistochemistry. Activation of the Wnt signaling pathway was evaluated by PCR array, RT-PCR, western blotting and immunofluorescence. XAV-939, a Wnt signaling pathway antagonist, was further used to determine whether the effect of melatonin on chondrocyte hypertrophic differentiation was mediated occurred by activation of Wnt signaling pathway.ResultsHistological staining showed melatonin increased chondrocyte cell volume and the expression of type X collagen but decreased the expression of type II collagen compared with the control group. RT-PCR showed that melatonin significantly up-regulated the gene expressions of biomarkers of hypertrophic chondrocytes, including type X collagen, alkaline phosphatase, runt-related transcription factor 2, Indian hedgehog and parathyroid hormone-related protein receptor, and melatonin down-regulated the mRNA expression of hallmarks of chondrocytes, including parathyroid hormone-related protein. PCR array showed that the effect of melatonin on chondrocyte hypertrophic differentiation was accompanied by the up-regulation of multiple target genes of the canonical Wnt signaling pathway, and this effect was blocked by XAV-939.ConclusionsThe current findings demonstrate that melatonin enhances the hypertrophic differentiation of MSC-derived chondrocytes through the Wnt signaling pathway. Our findings add evidence to the role of melatonin in promoting bone development and highlight the positive effects of melatonin on terminal differentiation of chondrocytes.
Highlights
Endochondral ossification (EO), one of the main processes in skeletal development in vertebrates, involves the progressive replacement of cartilaginous tissues by bony tissues for normal bone architecture formation [1, 2]
The current findings demonstrate that melatonin enhances the hypertrophic differentiation of Mesenchymal stem cell (MSC)-derived chondrocytes through the Wnt signaling pathway
Melatonin promotes hypertrophic differentiation of MSC‐derived chondrocytes Hypertrophy contributes to an increase in the volume of an organ or tissue based on the enlargement of component cells
Summary
Endochondral ossification (EO), one of the main processes in skeletal development in vertebrates, involves the progressive replacement of cartilaginous tissues by bony tissues for normal bone architecture formation [1, 2]. The growth plate is subdivided into three structurally and functionally independent zones: the resting zone, which contains round chondrocytes; the proliferative zone, which contains flattened chondrocytes; and the hypertrophic zone, which contains enlarged chondrocytes. These zones are spatially located from both ends to the middle along the vertical axis of the long bone [4, 5]. Chondrocyte hypertrophic differentiation has been highlighted as the pivotal stage in EO. Hypertrophy is a critical process for chondrocyte differentiation and maturation during endochondral ossification, which is responsible for the formation of long bone and postnatal longitudinal growth. Little is known about the effects of melatonin on the terminal differentiation of chondrocytes
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