Strategies for the application of miRNA-targeted therapy in the treatment of osteoporosis

Abstract

BACKGROUND: Studies have shown that miRNAs, as important post-transcriptional regulators of genes, play a key role in the onset and progression of osteoporosis. Through in-depth research on the biology of miRNA regulation of osteoporosis, its potential healing mechanisms have been revealed, and this field has become a hot focus of current research. OBJECTIVE: To explore the regulatory role of miRNAs in the development of osteoporosis and their molecular mechanisms, and to provide an overview of the key difficulties encountered in the therapeutic strategies for osteoporosis targeting miRNAs and their solutions. METHODS: We searched PubMed, Web of Science and CNKI databases for relevant literature published up to March 2025. The search terms were “miRNA, osteoporosis, angiogenesis, osteogenesis, gene therapy, drug delivery” in English and “miRNA, osteoporosis, gene therapy, ribonucleic acid drugs, delivery carrier” in Chinese. After reading the titles and abstracts for preliminary screening, we excluded the literature with poor relevance, old information, or repetitive views and lack of authority, and finally included 138 papers for review. RESULTS AND CONCLUSION: (1) miRNAs are highly efficient non-coding RNAs with a wide range of applications that can precisely regulate cellular activities, and they show significant therapeutic potential in regulating osteoblast function and bone angiogenesis. (2) Although miRNA-based targeted drugs have entered preclinical research in other disease areas, clinical translation still faces challenges of insufficient nucleic acid stability in vivo and off-target effects. (3) To address these challenges, researchers have proposed various strategies, including precise targeting of miRNA target genes to reduce off-target effects; chemical modification to improve the stability of nucleic acid drugs in vivo; reducing nucleic acid production costs to advance research; and utilizing viral vectors, exosomes, and various biomaterials to optimize nucleic acid drug delivery routes. (4) Advances in technology continue to innovate in improving the performance of nucleic acid drug carriers, and in the future, precise and efficient drug delivery and targeted therapeutic effects will be achieved.

1. Introduction

Osteoporosis (OP) is a common metabolic bone disease characterized by reduced bone mass, deterioration of bone microarchitecture, and increased bone fragility, leading to a significantly elevated risk of fractures [1]. The pathogenesis of OP primarily stems from an imbalance between osteoclast and osteoblast function during bone remodeling [2-3]. Clinical studies have shown that existing osteoporosis treatments have numerous adverse effects, such as bisphosphonates causing gastrointestinal discomfort, osteonecrosis of the jaw, and atypical femoral fractures; estrogen increasing the risk of breast cancer; calcitonin causing fever and joint pain; denosumab leading to hypocalcemia, anaphylactic shock, or atrial fibrillation; raloxifene causing deep vein thrombosis and hot flashes; and thyroid hormone analogs causing hypercalcemia and hypercalciuria [4]. Therefore, there is a great need to develop novel, effective, and safer drugs with a wider therapeutic window.

miRNAs are non-coding single-stranded RNA molecules of 19-24 nucleotides in length in eukaryotes, primarily regulating gene expression by binding to the 3'-untranslated region of target mRNAs [5]. miRNAs participate in various cellular biological events and pathophysiological processes of diseases [6-8]. In 2007, SUGATANI et al. [9] discovered that miR-223 is a key factor in osteoclast differentiation, opening the research on miRNA regulation of bone metabolism. With ongoing research, a large number of miRNAs have been found to regulate bone remodeling by modulating transcription factors and signaling pathways related to bone metabolism. Additionally, certain hormones and drugs influence miRNA expression to intervene in the development of osteoporosis. For example, estrogen can regulate the expression of multiple miRNAs in bone cells, thereby affecting bone metabolism.