Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered the core pathological characteristic of steroid-associated osteonecrosis of the femoral head (SONFH). N6-Methyladenosine (m6A) is the most common type of RNA modification in eukaryotic cells and participates in various physiological and pathological processes. However, the relationship between m6A modification and SONFH has not been reported. In the present study, we aimed to explore the roles of m6A modifications and methyltransferase METTL14 in SONFH. Our results showed that the m6A levels were down-regulated in femoral head tissues and BMSCs from SONFH patients, and this effect was attributed to the reduction of METTL14. Furthermore, METTL14 overexpression in BMSCs from SONFH patients enhanced cell proliferation and osteogenic differentiation. We further identified PTPN6 as the downstream target of METTL14 by mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt signaling pathway, and this effect was caused by the interaction of PTPN6 and GSK-3β. In conclusion, we elucidated the functional roles of METTL14 and m6A methylation in SONFH BMSCs and identified a novel RNA regulatory mechanism, providing a potential therapeutic target for SONFH.
Study Design:
An observational prospective cohort study.
Objective:
To investigate the influence of natural history on the recovery of patients with cervical spondylotic myelopathy (CSM) after anterior cervical decompression.
Summary of Background Data:
The natural history of CSM has not been clearly elucidated, it remains unclear whether the natural history of CSM is associated with the recovery process after surgical treatment.
Materials and Methods:
Patients with CSM (n=117) after anterior cervical decompression were stratified variously on the basis of natural history features. Baseline and postoperative neurological functions were rated using the Japanese Orthopaedic Association (JOA) and patient-based self-evaluation (PBSE) scores. The minimum and maximum recovery times for sensory function, and motor functions of the upper and lower extremities were analyzed separately at time points 1–60 months after surgery.
Results:
In all patients, the postoperative JOA and PBSE scores were significantly improved relative to baseline, in which sensory function recovered most quickly, followed by upper-extremity and lower-extremity motor functions. However, when compared with patients whose first symptom onset at the lower extremity, patients with the first onset at the upper extremity required less time to recover lower-extremity motor function, but more time to recover upper-extremity motor function. Patients with rapid progression had significantly lower preoperative and final JOA and PBSE scores compared with patients whose progression was steady or stepwise. Patients with preoperative symptoms ≥1 year had longer recovery time and poorer functional outcomes compared with those symptoms <1 year.
Conclusions:
In patients with CSM, the location of first symptom onset, progressive velocity of symptom, and duration of preoperative symptoms significantly influenced the recovery process after anterior cervical decompression.
Level of Evidence:
Level 2—observational prospective study.
Circular RNA is an innovative kind of endogenous non-coding RNA, which could take part in tumorigenesis. Nonetheless, the potential molecular mechanisms of circVRK1 in the progression of osteosarcoma remain unresolved. In the current study, we initially investigated circVRK1 levels in osteosarcoma clinical samples and cell lines by qRT-PCR analysis and northern blot assay. RNase R treatments, RNA stability assay and nucleoplasmic separation assay were conducted to identify the characteristics of circVRK1. We adopted CCK-8, colony formation, wound-healing, and transwell assays to assess the biological effects of circVRK1 on the proliferation, migration, and invasiveness of osteosarcoma cells in vitro. We then constructed a xenograft model in nude mice to confirm the suppressive role of circVRK1 in vivo. Moreover, dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays were utilized to elucidate the underlying molecular mechanisms mediated by circVRK1. We demonstrated that circVRK1 was a stable circular transcript localized in the cytoplasm of osteosarcoma cells, and the down-regulation of circVRK1 in osteosarcoma tissues was related to poor outcome of patients. Meanwhile, over-expressed circVRK1 obviously restrained the growth, migration, and invasion of osteosarcoma in vitro and in vivo. Mechanistically, circVRK1 was assumed to be a microRNA sponge for miR-337-3p, and ZNF652 was the downstream gene of miR-337-3p. CircVRK1 overexpression or miR-337-3p knockdown accelerated ZNF652 expression, and up-regulated miR-337-3p efficiently abolished the promotion of ZNF652 induced by circVRK1. Moreover, rescue experiments have proved that circVRK1 inhibits the progression of osteosarcoma by modulating the miR-337-3p/ZNF652 axis. Therefore, we conclude that circVRK1 promotes ZNF652 expression by sponging miR-337-3p. CircVRK1 serves as a molecule sponge for miR-337-3p and mediates the ceRNA network to promote the expression of ZNF652, thus suppresses osteosarcoma proliferation, migration and invasion.
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