TGF‐β/SMAD signaling inhibits intermittent cyclic mechanical tension‐induced degeneration of endplate chondrocytes by regulating the miR‐455‐5p/RUNX2 axis

Abstract

A mechanical stimulation plays a pivotal role in maintaining normal cartilage function. Our objective was to reveal the mechanism of action of the tension-sensitive molecule miR-455-5p in the degeneration of endplate chondrocytes and to identify whether the transforming growth factor beta (TGF-β)/SMAD signaling pathway has a regulatory effect on it. The expression profiles of members of the TGF-β/SMAD pathway, miR-455-5p, and RUNX2 were determined by microRNA microarray analysis, reverse transcription quantitative polymerase chain reaction, luciferase reporter assay, and Western blot analysis. Intermittent cyclic mechanical tension (ICMT) induced the degeneration of endplate chondrocytes without affecting their viability. The tension-sensitive molecule miR-455-5p specifically bound to RUNX2, a gene involved in the degeneration of endplate chondrocytes. Activation of the TGF-β/SMAD signaling pathway upregulated miR-455-5p expression and thus inhibited RUNX2 levels. Therefore, the TGF-β/SMAD signaling pathway inhibits the ICMT-induced degeneration of endplate chondrocytes by regulating the miR-455-5p/RUNX2 axis.

Molecular Mechanisms of Chondrocyte Proliferation and Differentiation

“…example, Runx2, Sox9, BMP) affects cartilage development. The expression of Runx2 is suppressed by the activation of the TGF-β/Smads signaling, thereby reducing chondrocyte ECM degradation (Xiao et al, 2018;Janssen et al, 2019). On the contrary, Sox9 protein level can be stabilized by TGF-β, and both of them synergistically protect chondrocytes' function (Chavez et al, 2017).…”

circRNA_0058097 promotes tension‐induced degeneration of endplate chondrocytes by regulating HDAC4 expression through sponge adsorption of miR‐365a‐5p

“…23,24 Therefore, clarification of the molecular mechanism underlying tension-induced endplate chondrocyte degeneration and enhancement of stress resistance may be crucial to delay or reverse early degeneration of endplate cartilage. 25 CircRNA is a special type of noncoding RNA molecule. In contrast to traditional linear RNAs, circRNA has a closed-loop structure and exists extensively in eukaryotic transcripts.…”

“…However, short‐term tension stimulation does not weaken the viability of endplate chondrocytes, suggesting that tension stimulation does not directly bring about the death of endplate chondrocytes when first loaded, but instead leads to endplate chondrocyte degeneration through other signaling pathways . Therefore, clarification of the molecular mechanism underlying tension‐induced endplate chondrocyte degeneration and enhancement of stress resistance may be crucial to delay or reverse early degeneration of endplate cartilage …”

Role of microRNAs in intervertebral disc degeneration (Review)

“…miR-365 is a mechanically sensitive miRNA, which directly targets histone deacetylase 4 to regulate the degeneration of human chondrocytes (114). In addition, the TGF-β/SMAD signaling pathway inhibits the intermittent cyclic mechanical tension-mediated degeneration of CEP chondrocytes by regulating the miR-455-5p/Runt-related transcription factor 2 (Runx2) axis (115). In addition, it was previously demonstrated that miR-20a/ankylosis protein homolog regulates stiff matrix-promoted CEP calcification (116).…”