Regulatory effect of miR‑421 on humeral fracture and heterotopic ossification in elderly patients

Abstract

The present study aimed to investigate the role of miR-421 and bone morphogenetic protein-2 (BMP-2) in the bone tissues and blood of elderly patients with humeral fractures and heterotopic ossification. A total of 38 patients with humeral fractures, including 16 patients who received surgery within 1-7 days of fracture and 22 patients who received surgery within 8-14 days of fracture, were enrolled. An additional 18 patients who had heterotopic ossification and 26 patients who had humeral fracture and not heterotopic ossification were also included. Bone tissues and blood were collected. Reverse transcription-quantitative polymerase chain reaction was performed to determine the miR-421 and BMP-2 mRNA expression levels in the samples. Western blotting and ELISA were performed to detect BMP-2 protein levels in bone tissues and blood, respectively. Dual-luciferase reporter assays were performed to verify whether BMP-2 is the direct target gene of miR-421. Compared with the patients who received surgery 1-7 days after fracture, the patients who accepted the surgery 8-14 days after fracture had significantly increased levels of BMP-2 mRNA and protein in their bone tissues and blood (P<0.05). Contrastingly, the expression level of miR-421 decreased in the samples from patients who accepted the surgery 8-14 days after fracture compared with the level in those who received surgery 1-7 days after fracture (P<0.05). Compared with the patients without heterotopic ossification, the patients with heterotopic ossification had increased BMP-2 mRNA and protein expression levels in their bone tissues and blood, whereas the expression of miR-421 was significantly decreased (P<0.05). The dual-luciferase reporter assay demonstrated that BMP-2 was the direct target gene of miR-421. The upregulation of BMP-2 may be associated with the downregulation of miR-421. miR-421 may regulate the recovery of humeral fracture and heterotopic ossification through BMP-2. The results of the present study may provide a theoretical basis for the diagnosis and treatment of humeral fracture and heterotopic ossification.

The Kinesin Gene KIF26B Modulates the Severity of Post-Traumatic Heterotopic Ossification

“…BMP signaling is transduced via p38 mitogen-activated protein kinase (MAPK) [ 39 ] and/or SMAD complexes [ 40 ]. The canonical Wnt /ß-catenin pathway is also implicated in chondrocyte maturation and osteoblast differentiation [ 41 , 42 ]. A recent study showed that TNF inhibited BMP2-mediated osteogenesis via a strong activation of p38 MAPK in C2C12 and MC3T3-E1 cells whilst inhibition of p38 rescued the expression of RUNX2 and other osteogenic markers induced by BMP2 [ 43 ].…”

Pathophysiology and Emerging Molecular Therapeutic Targets in Heterotopic Ossification

“…These pathways should not be viewed as independent, as crosstalk between them occurs [117][118][119][120]. BMP2 is overexpressed in clinically evolving HO tissue after trauma [121,122]. Augmented BMP signalling also occurs following trauma-induced HO development in animal models whilst BMP antagonism reduces HO severity [123,124].…”

The role of miRNA and lncRNA in heterotopic ossification pathogenesis

“…However, patients with HO show significantly lower expression of miR421 in their bone and blood, compared to patients who did not develop HO. Thus, miR421 could play a regulatory role in the HO induction [ 180 ]. It was documented that BMP2, i.e., the strongest osteogenic induction factor, was the direct target of miR421.…”

“…Verification of the role of BMP2 in patients with HO induced by humeral fracture showed a significantly increased expression of BMP2 in ossified tissues and blood. Therefore, the development of HO may be related to the up-regulation of BMP2 and down-regulation of miR421 [ 180 ].…”