Bone marrow-derived mesenchymal stem cells (BMSCs) have been suggested to possess the capacity to differentiate into different cell lineages. Maintaining a balanced stem cell differentiation program is crucial to the bone microenvironment and bone development. MicroRNAs (miRNAs) have played a critical role in regulating the differentiation of BMSCs into particular lineage. However, the role of miR-149-3p in the adipogenic and osteogenic differentiation of BMSCs has not been extensively discovered. In this study, we aimed to detect the expression levels of miR-149-3p during the differentiation of BMSCs and investigate whether miR-149-3p participated in the lineage choice of BMSCs or not. Compared with mimic-negative control (NC), miR-149-3p mimic decreased the adipogenic differentiation potential of BMSCs and increased the osteogenic differentiation potential. Further analysis revealed that overexpression of miR-149-3p repressed the expression of fat mass and obesity-associated (FTO) gene through binding to the 3ʹ UTR of the FTO mRNA. Also, the role of miR-149-3p mimic in inhibiting adipogenic lineage differentiation and potentiating osteogenic lineage differentiation was mainly through targeting FTO, which also played an important role in regulating body weight and fat mass. In addition, BMSCs treated with miR-149-3p anti-miRNA oligonucleotide (AMO) exhibited higher potential to differentiate into adipocytes and lower tendency to differentiate into osteoblasts compared with BMSCs transfected with NC. In summary, our results detected the effects of miR-149-3p in cell fate specification of BMSCs and revealed that miR-149-3p inhibited the adipogenic differentiation of BMSCs via a miR-149-3p/FTO regulatory axis. This study provided cellular and molecular insights into the observation that miR-149-3p was a prospective candidate gene for BMSC-based bone tissue engineering in treating osteoporosis.

Objectives: To synthesize existing evidence on prevalence as well as clinical and socio-economic aspects of Long COVID.Methods: An umbrella review of reviews and a targeted evidence synthesis of their primary studies, including searches in four electronic databases, reference lists of included reviews, as well as related article lists of relevant publications.Results: Synthesis included 23 reviews and 102 primary studies. Prevalence estimates ranged from 7.5% to 41% in non-hospitalized adults, 2.3%–53% in mixed adult samples, 37.6% in hospitalized adults, and 2%–3.5% in primarily non-hospitalized children. Preliminary evidence suggests that female sex, age, comorbidities, the severity of acute disease, and obesity are associated with Long COVID. Almost 50% of primary studies reported some degree of Long COVID-related social and family-life impairment, long absence periods off work, adjusted workloads, and loss of employment.Conclusion: Long COVID will likely have a substantial public health impact. Current evidence is still heterogeneous and incomplete. To fully understand Long COVID, well-designed prospective studies with representative samples will be essential.

Methyltransferase-like 3 (METTL3) is the main enzyme for N6-methyladenosine (m6A)-based methylation of RNAs and it has been implicated in many biological and pathophysiological processes. In this study, we aimed to explore the potential involvement of METTL3 in osteoblast differentiation and decipher the underlying cellular and molecular mechanisms. We demonstrated that METTL3 is downregulated in human osteoporosis and the ovariectomized (OVX) mouse model, as well as during the osteogenic differentiation. Silence of METTL3 by short interfering RNA (siRNA) decreased m6A methylation levels and inhibited osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) and reduced bone mass, and similar effects were observed in METTL3+/− knockout mice. In contrast, adenovirus-mediated overexpression of METTL3 produced the opposite effects. In addition, METTL3 enhanced, whereas METTL3 silence or knockout suppressed, the m6A methylations of runt-related transcription factor 2 (RUNX2; a key transcription factor for osteoblast differentiation and bone formation) and precursor (pre-)miR-320. Moreover, downregulation of mature miR-320 rescued the decreased bone mass caused by METTL3 silence or METTL3+/− knockout. Therefore, METTL3-based m6A modification favors osteogenic differentiation of BMSCs through m6A-based direct and indirect regulation of RUNX2, and abnormal downregulation of METTL3 is likely one of the mechanisms underlying osteoporosis in patients and mice. Thus, METTL3 overexpression might be considered a new approach of replacement therapy for the treatment of human osteoporosis.

No abstract

Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to differentiate into osteoblasts or adipocytes, and the shift between osteogenic and adipogenic differentiation determines bone mass. The aim of this study was to identify whether lncRNAs are involved in the differentiation commitment of BMSCs during osteoporosis. Here, we found ORLNC1, a functionally undefined lncRNA that is highly conserved, which exhibited markedly higher expression levels in BMSCs, bone tissue, and the serum of OVX-induced osteoporotic mice than sham-operated counterparts. Notably, a similar higher abundance of lncRNA-ORLNC1 expression was also observed in the bone tissue of osteoporotic patients. The transgenic mice overexpressing lncRNA-ORLNC1 showed a substantial increase in the osteoporosis-associated bone loss and decline in the osteogenesis of BMSCs. The BMSCs pretreated with lncRNA-ORLNC1-overexpressing lentivirus vector exhibited the suppressed capacity of osteogenic differentiation and oppositely enhanced adipogenic differentiation. We then established that lncRNA-ORLNC1 acted as a competitive endogenous RNA (ceRNA) for miR-296. Moreover, miR-296 was found markedly upregulated during osteoblast differentiation, and it accelerated osteogenic differentiation by targeting Pten. Taken together, our results indicated that the lncRNA-ORLNC1-miR-296-Pten axis may be a critical regulator of the osteoporosis-related switch between osteogenesis and adipogenesis of BMSCs and might represent a plausible therapeutic target for improving osteoporotic bone loss.

Osteoporosis is closely associated with the dysfunction of bone metabolism, which is caused by the imbalance between new bone formation and bone resorption. Osteogenic differentiation plays a vital role in maintaining the balance of bone microenvironment. The present study investigated whether melatonin participated in the osteogenic commitment of bone marrow mesenchymal stem cells (BMSCs) and further explored its underlying mechanisms. Our data showed that melatonin exhibited the capacity of regulating osteogenic differentiation of BMSCs, which was blocked by its membrane receptor inhibitor luzindole. Further study demonstrated that the expression of miR‐92b‐5p was up‐regulated in BMSCs after administration of melatonin, and transfection of miR‐92b‐5p accelerated osteogenesis of BMSCs. In contrast, silence of miR‐92b‐5p inhibited the osteogenesis of BMSCs. The increase in osteoblast differentiation of BMSCs caused by melatonin was attenuated by miR‐92b‐5p AMO as well. Luciferase reporter assay, real‐time qPCR analysis and western blot analysis confirmed that miR‐92b‐5p was involved in osteogenesis by directly targeting intracellular adhesion molecule‐1 (ICAM‐1). Melatonin improved the expression of miR‐92b‐5p, which could regulate the differentiation of BMSCs into osteoblasts by targeting ICAM‐1. This study provided novel methods for treating osteoporosis.

Evidence, demonstrating long noncoding RNAs (lncRNAs) as critical players in cancer, remains to increase. lncRNA SBF2‐AS1 was reported to be involved in several cancers, such as hepatocellular carcinoma. However, the role of SBF2‐AS1 in colorectal cancer (CRC) is unknown. We showed lncRNA SBF2‐AS1 expression was growing in CRC samples, especially in advanced cases. Accordingly, SBF2‐AS1 possesses higher expression in CRC cell lines than in normal cell line. Moreover, SBF2‐AS1 high expression indicated a low survival rate. Functionally, SBF2‐AS1 knockdown suppressed the proliferation, migration, and invasion of CRC cells. In terms of mechanism, SBF2‐AS1 upregulation restrained the activity of miR‐619‐5p and led to overexpression of HDAC3. Importantly, downregulation of miR‐619‐5p or HDAC3 overexpression reversed SBF2‐AS1‐silencing‐caused suppression on proliferation and metastasis. Summarily, our findings elucidated a crucial role of SBF2‐AS1 as a miR‐619‐5p sponge, shedding novel light on lncRNA‐related prognostics.

No abstract