Mechanisms of miRNAs involved in cartilage development: new strategies and targets

Abstract

BACKGROUND: The molecular regulation of cartilage development is one of the key scientific issues in the field of orthopedics. MicroRNAs (miRNAs), as important regulators of gene expression, regulate post-transcriptional silencing or translation inhibition by binding to the 3' untranslated region (UTR) of target mRNAs, and are involved in the regulation of cell differentiation, proliferation, and metabolic homeostasis. In recent years, studies have found that miRNAs play an important role in cartilage development and various cartilage-related diseases, and their abnormal expression is closely related to diseases such as skeletal dysplasia and osteoarthritis. In-depth research on the mechanisms of miRNAs in cartilage development is of great significance for understanding the fate determination of chondrocytes and the pathogenesis of related diseases. OBJECTIVE: To comprehensively summarize the mechanisms of miRNAs in cartilage development, explore their regulatory roles in chondrocyte differentiation, proliferation, and apoptosis, and their functions in disease states such as osteoarthritis and chondrodysplasia, providing a theoretical basis for the prevention and treatment of related diseases. METHODS: PubMed, CNKI, Wanfang, and VIP databases were searched from inception to June 2025, supplemented by manual retrieval of relevant books. High-quality literature on miRNA regulation of cartilage development was screened, prioritizing studies published within the last 10 years. A total of 99 articles (95 in English, 4 in Chinese) were included for systematic analysis and summary. RESULTS AND CONCLUSION: Studies have shown that miRNAs precisely regulate key transcription factors, signaling pathways, and epigenetic modifications, thereby influencing chondrocyte differentiation, proliferation, and apoptosis. In disease states, abnormal miRNA expression is closely related to various cartilage diseases. These findings not only reveal the direct regulatory role of miRNAs in cartilage development but also provide new strategies and targets for the diagnosis, prognosis, and treatment of related diseases. With the continuous development of cutting-edge technologies such as gene editing, single-cell sequencing, and bioinformatics, the application of miRNA research in cartilage development and diseases has made significant progress, promising new means for early diagnosis, precise treatment, and prognosis assessment of skeletal diseases.

1. Introduction

The molecular regulatory mechanisms of cartilage development have always been a core scientific issue in orthopedics. MicroRNAs (miRNAs) are a large family of single-stranded RNAs composed of 17–25 nucleotides that regulate post-translational levels of more than 60% of protein-coding genes in the human genome. Dysregulation of miRNAs is associated with various human diseases, including skeletal dysplasia and cartilage disorders [1]. In mammals, miRNAs mediate post-transcriptional silencing or translational inhibition by sequence-specific binding to the 3' untranslated region of target mRNAs, deeply participating in the regulation of cell differentiation, proliferation, and metabolic homeostasis.

In recent years, breakthrough progress in orthopedics has shown that miRNAs play key roles in the directed differentiation of chondrocyte progenitors, the balance of extracellular matrix synthesis and degradation, and cartilage-to-bone transformation [2]. With the popularization of high-throughput sequencing technology, researchers have for the first time identified specific high expression of miR-140 in human cartilage tissue. Subsequent studies found that miR-140 drives chondrocyte differentiation by targeting and inhibiting histone deacetylase 4, thereby activating the sex-determining region Y-box 9 transcription factor [3]. This discovery not only revealed the direct regulatory role of miRNAs in cartilage development but also opened a new dimension in the study of epigenetic regulatory mechanisms.

Recent research further clarified that miR-199a-5p affects the hypoxic stress response of chondrocytes by regulating the hypoxia-inducible factor 1α/matrix metalloproteinase 1 axis, providing a new perspective on the molecular mechanisms of degenerative joint diseases [4]. Notably, the application of single-cell sequencing technology has enabled researchers to resolve the spatiotemporal specific expression profiles of miRNAs during cartilage development. However, current research still faces three core challenges: first, the high complexity of miRNA regulatory networks leads to tissue-specific paradoxes in their functions; for example, miR-221 delays hypertrophic differentiation in chondrocytes by inhibiting SMAD family member 3, but in osteoblasts it promotes mineralization by activating Runt-related transcription factor 2, and the molecular basis of this dual function has not been fully elucidated. Second, existing technical systems have limitations in dynamic monitoring and targeted intervention of miRNAs.