A MicroRNA-124 Polymorphism is Associated with Fracture Healing via Modulating BMP6 Expression

Abstract

Background: miR-124-3p has been reported to be involved in the pathogenesis of many diseases by modulating a variety of signaling pathways. In this study, we aimed to understand the impact of miR-124-3p expression level on the fracture healing in the patients of metaphyseal fracture of distal tibia, who received minimal invasive percutaneous plate osteosynthesis. Methods: We firstly collected 195 patients of metaphyseal fracture of distal tibia, and the genotype of rs531564 was determined: GG (n=124) and GC+CC (n=71). We collected information of the participants including age, gender, total in-hospital time, smoking and alcohol consumption. Subsequently, we searched the miRNA database online to identify the possible binding sequence of miR-124-3p located within the 3’-UTR of the target gene. We did correlation analysis and luciferase to understand the regulatory relationship between miR-124-3p and BMP6. Meanwhile, we also conducted real time PCR and western blotting analysis to study the mRNA and protein expression level of BMP6 in different genotype groups. We then treated the cells with scramble control, miR-124-3p mimics, BMP6 siRNA and miR-124-3p inhibitors to investigate the influence of miR-124-3p on the expression of BMP6, viability and apoptosis of cells. Results: Total in-hospital time was significantly longer in GC+CC group than GG group. MiR-124-3p was up-regulated in GG group than GC and CC groups. BMP6 was virtual target of miR-124-3p. There existed negative regulatory relationship betweenmiR-124-3p and BMP6. The mRNA and protein expression level of BMP6 decreased in GG group. MiR-124-3p decreased the expression of BMP6. MiR-124-3p negatively interfered with the viability of cells and BMP6 positively interfered with the viability of cells. MiR-124-3p reduced apoptosis and BMP6 promoted apoptosis. Conclusion: These data proved the expression of miR-124-3p was associated with the healing of metaphyseal fracture of distal tibia, and could be recognized as a biomarker to predict the healing of metaphyseal fracture of distal tibia.

The Therapeutic Potential of MicroRNAs as Orthobiologics for Skeletal Fractures

“…More importantly, BMP‐6 mRNA and protein expression levels were significantly decreased in the GG group compared with GC and CC groups, confirming a negative regulatory relationship between miR‐124‐3p and BMP‐6. The results suggest that the rs531564 miRNA‐124‐3p polymorphism may serve as a biomarker for metaphyseal distal tibia fractures …”

“…In addition to profiling studies, researchers have begun to report on the association of miRNA polymorphisms with clinical fractures. For example, one study focused on the effect of miR‐124‐3p expression levels in 195 patients with metaphyseal fractures of the distal tibia . Specifically, the study investigated the presence of the genotype of rs531564 (a single‐nucleotide polymorphism [SNP], site in pri‐miR‐124) by dividing the patients into two groups by the genotypes, GG ( n = 124) and GC + CC ( n = 71), and found that miR‐124‐3p expression was significantly increased in the GG group compared with the GC and CC groups.…”

“…The results suggest that the rs531564 miRNA-124-3p polymorphism may serve as a biomarker for metaphyseal distal tibia fractures. (38) Similarly, a case-control association study was conducted to determine the link between miR-146a, miR-149, miR-196a2, and miR-499 (based on previous reports of their effects on skeletal cells) polymorphisms and osteoporotic vertebral compression fracture (OVCF) susceptibility. (39) A total of 286 unrelated postmenopausal Korean women (57 with OVCFs, 55 with non-OVCFs, and 174 healthy controls) were recruited and four SNPs from pre-miRNA sequences miR-146aC>G (rs2910164), miR-149T>C (rs2292832), miR-196a2T>C (rs11614913), and miR-499A>G (rs3746444) were examined.…”

Underlying Signaling Pathways and Therapeutic Applications of Pulsed Electromagnetic Fields in Bone Repair

“…The interaction of TGF-βs/BMPs with TGF-β specific type 1 and type 2 or BMP serine/threonine kinase receptors initiates the signaling cascade via canonical (or Smad-dependent pathways) and non-canonical pathways (or Smad-independent signaling pathways) [50]. The TGF-β/BMP signaling pathway plays an important regulatory role in bone repair [51-56]. It is also confirmed to be involved in PEMF-induced osteogenesis.…”

Improving Bone Regeneration Using Chordin siRNA Delivered by pH-Responsive and Non-Toxic Polyspermine Imidazole-4,5-Imine

“…The migration and osteogenic differentiation of BMSCs are tightly regulated by various cellular signals [3][4][5][6][7][8], and in vitro and in vivo studies have shown that bone morphogenetic proteins (BMPs) play a critical role in osteogenic differentiation and bone formation [9][10][11]. BMPs combine with type I and II receptors on the cell surface to form a complex and activate the Smad signalling pathways, which regulate osteogenic gene expression [12,13], suggesting that manipulation of BMP signalling may be employed as a therapeutic approach to treat bone nonunion. However, this technique has several key disadvantages, as these factors must be used at supraphysiological concentrations, are shortlived and expensive, and result in many side effects [14][15][16][17].…”