Osteoporosis (OP) is a metabolic bone disease syndrome characterized by osteopenia and destruction of bone microarchitecture. Patients have decreased osteogenic strength, increased fragility, and are prone to fractures. Postmenopausal osteoporosis, also known as type I OP, generally occurs about 10 years after menopause, and is most commonly seen clinically in women aged 60–80 . At present, more than 200 million people in the world suffer from osteoporosis, and there are more than 88 million in China, and its incidence has jumped to the 7th place of common diseases and morbidities. The underlying cause is an imbalance between osteoclastic bone resorption and osteoblastic bone formation, resulting in a decrease in bone mass and structural changes in bone tissue, which increases bone fragility and leads to fractures. Epidemiological studies in North America have shown that the risk of osteoporotic fractures in white women over 50 years of age is 17.5% for hip fractures, 15.6% for vertebral fractures and 16.9% for distal forearm fractures; the corresponding risks for men are 6.0%, 5.0% and 3.0% respectively . These fractures (especially hip fractures) have a high incidence, poor prognosis, high disability rate and high medical costs, often causing a large financial burden to the patient, family and society. Therefore, the prevention and treatment of fractures in patients with postmenopausal osteoporosis (OPM) is one of the hot topics of clinical research in internal medicine and orthopaedic clinical research in recent years. However, the current clinical treatment of OPM is mainly based on hormone replacement, calcium supplementation and inhibition of bone resorption, but the treatment is not effective due to drug toxicity, malabsorption, unstable efficacy and poor patient compliance.
Bone marrow mesenchymal stem cells (BMMSCs) are adult stem cells derived from mesoderm with self-renewal and multi-directional differentiation potential . BMMSCs play an important role in bone development, regeneration and repair by differentiating into various cells. BMMSCs are the source cells of both osteoblasts and adipocytes, and the balance of their osteogenic-adipogenic differentiation capacity is closely related to the homeostatic balance of bone remodeling. In the process of osteoporosis, the osteogenic differentiation ability of BMMSCs decreases, while the adipogenic differentiation ability increases. This may be one of the reasons for osteoporosis, but the specific regulatory mechanism of the multi-directional differentiation of BMMSCs is still unclear.
MicroRNAs (miRNAs) are a newly discovered class of small non-coding RNAs that widely exist in animals and plants, and can bind to the 3′-untranslated region of target genes in a base-pairing manner . The miRNA can silence the expression of target genes at the post-transcriptional level, and play important regulatory roles in a variety of physiological and pathological processes. A variety of miRNAs have been identified that are involved in the osteogenic-adipogenic differentiation process of stem cells and play an important role in regulating stem cell fate. However, it is still unclear which miRNAs play key roles in the multidirectional differentiation of BMMSCs, the molecular signaling pathways that specifically regulate the differentiation of BMMSCs, and whether miRNAs play a role in the occurrence and development of OPM.
In this study, BMMSCs were isolated and purified from normal mice and osteoporosis model mice . It has been reported that miR-705 abnormally regulates the differentiation of bone marrow mesenchymal stem cells in postmenopausal osteoporotic mice. Studies have shown that BMMSCs from two sources, post-O-BMMSCs and post-S-BMMSCs, both express normal mesenchymal stem cell surface markers, but do not express hematopoietic system-derived cell surface markers, and have clonogenic ability. The osteogenic differentiation ability of O-BMMSCs was significantly lower than S-BMMSCs after osteogenic induction, while the adipogenic differentiation ability of O-BMMSCs after adipogenic induction was significantly higher than S-BMMSCs. Gene screening revealed that miR-181c-5p was differentially expressed between normal mice and osteoporosis model mice. In this experiment, miR-181c-5p was selected for further functional study.
The miR-181 family is an evolutionarily conserved family of microRNAs with a wide range of functions involved in the regulation of immune system function , vascular inflammatory response , and haematopoietic development . In addition, the miR-181 family is aberrantly expressed in a variety of tumors, however the role in osteogenic differentiation is not reported. In osteoporosis caused by estrogen deficiency, high expression of miR-181a can inhibit the proliferation of BMMSCs and reduce the osteogenic capacity of bone marrow stromal cells, which may be one of the important factors affecting the pathogenesis of osteoporosis . In addition, miR-181b was found to significantly reduce the osteogenic differentiation ability of BMMSCs in vitro .
This study further explored the role and mechanism of miR-181c-5p in the pathogenesis of OPM, both to deepen the understanding of the molecular mechanism of OPM pathogenesis and to clarify the underlying causes of bone loss in osteoporosis, and to provide important guidance for the prevention and treatment of various postmenopausal osteoporosis-induced fracture diseases.