The alteration of age‐related molecules in the bone marrow microenvironment is one of the driving forces in osteoporosis. These molecules inhibit bone formation and promote bone resorption by regulating osteoblastic and osteoclastic activity, contributing to age‐related bone loss. Here, we observed that the level of microRNA‐31a‐5p (miR‐31a‐5p) was significantly increased in bone marrow stromal cells (BMSCs) from aged rats, and these BMSCs demonstrated increased adipogenesis and aging phenotypes as well as decreased osteogenesis and stemness. We used the gain‐of‐function and knockdown approach to delineate the roles of miR‐31a‐5p in osteogenic differentiation by assessing the decrease of special AT‐rich sequence‐binding protein 2 (SATB2) levels and the aging of BMSCs by regulating the decline of E2F2 and recruiting senescence‐associated heterochromatin foci (SAHF). Notably, expression of miR‐31a‐5p, which promotes osteoclastogenesis and bone resorption, was markedly higher in BMSCs‐derived exosomes from aged rats compared to those from young rats, and suppression of exosomal miR‐31a‐5p inhibited the differentiation and function of osteoclasts, as shown by elevated RhoA activity. Moreover, using antagomiR‐31a‐5p, we observed that, in the bone marrow microenvironment, inhibition of miR‐31a‐5p prevented bone loss and decreased the osteoclastic activity of aged rats. Collectively, our results reveal that miR‐31a‐5p acts as a key modulator in the age‐related bone marrow microenvironment by influencing osteoblastic and osteoclastic differentiation and that it may be a potential therapeutic target for age‐related osteoporosis.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection (LRTI) in children from infancy up to early childhood. Recently, we demonstrated that RSV infection alters cellular small non-coding RNA (sncRNA) expression, most notably the tRNA-derived RNA fragments (tRFs). However, the functions of the tRFs in virus-host interaction are largely unknown. Herein, we examined the role of three RSV-induced tRFs derived from the 5-end of mature tRNAs decoding GlyCCC, LysCTT and CysGCA (named tRF5-GlyCCC, tRF5-LysCTT and tRF5-CysGCA, respectively) in controlling RSV replication. We found that tRF5-GlyCCC and tRF5-LysCTT, but not tRF5-CysGCA, promote RSV replication, demonstrating the functional specificity of tRFs. The associated molecular mechanisms underlying the functions of tRF5-GlyCCC and tRF5-LysCTT were also investigated. Regulating the expression and/or activity of these tRFs may provide new insights into preventive and therapeutic strategies for RSV infection. The study also accumulated data for future development of a tRF targeting algorithm.

Bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a detrimental side effect of the long‐term administration of bisphosphonates. Although macrophages were reported to be an important mediator of BRONJ, the detailed potential mechanism of BRONJ remains unclear. Here, we reported an elevated TLR‐4 expression in macrophages under action of zoledronic acid (ZA), resulting in enhanced M1 macrophage polarization and decreased M2 macrophage polarization both in vitro and in vivo. After inhibiting the TLR‐4 signaling pathway, the activation of the TLR‐4/NF‐κB signaling pathway and the induction of NF‐κB nuclear translocation and production of proinflammatory cytokines by ZA were suppressed in macrophages, thereby inhibiting M1 macrophage polarization. By utilizing the TLR‐4−/− mice, development of BRONJ was markedly ameliorated, and M1 macrophages were significantly attenuated in the extraction socket tissues in the TLR‐4−/− mice. Importantly, the systemic administration of the TLR‐4 inhibitor TAK‐242 improved the wound healing of the extraction socket and decreased the incidence rate of BRONJ. Taken together, our findings suggest that TLR‐4‐mediated macrophage polarization participates in the pathogenesis of BRONJ in mice, and TLR‐4 may be a potential target for the prevention and therapeutic treatment of BRONJ.—Zhu, W., Xu, R., Du, J., Fu, Y., Li, S., Zhang, P., Liu, L., Jiang, H. Zoledronic acid promotes TLR‐4‐mediated M1 macrophage polarization in bisphosphonate‐related osteonecrosis of the jaw. FASEB J. 33, 5208–5219 (2019). http://www.fasebj.org

No abstract

tRNA-derived RNA fragments (tRFs) are an emerging class of non-coding RNAs (ncRNAs). A growing number of reports have shown that tRFs are not random degradation products but are functional ncRNAs made of specific tRNA cleavage. They play regulatory roles in several biological contexts such as cancer, innate immunity, stress responses, and neurological disorders. In this review, we summarize the biogenesis and functions of tRFs.

The dysfunction of bone marrow stromal cells (BMSCs) may be a core factor in Type 2 diabetes mellitus (T2DM) associated osteoporosis. However, the underlying mechanism is not well understood. Here, we delineated the critical role of insulin impeding osteogenesis of BMSCs in T2DM. Compared with BMSCs from healthy people (H-BMSCs), BMSCs from T2DM patient (DM-BMSCs) showed decreased osteogenic differentiation and autophagy level, and increased senescent phenotype. H-BMSCs incubated in hyperglycemic and hyperinsulinemic conditions similarly showed these phenotypes of DM-BMSCs. Notably, enhanced TGF-β1 expression was detected not only in DM-BMSCs and high-glucose and insulin-treated H-BMSCs, but also in bone callus of streptozocin-induced diabetic rats. Moreover, inhibiting TGF-β1 signaling not only enhanced osteogenic differentiation and autophagy level of DM-BMSCs, but also delayed senescence of DM-BMSCs, as well as promoted mandible defect healing of diabetic rats. Finally, we further verified that it was TGF-β receptor II (TβRII), not TβRI, markedly increased in both DM-BMSCs and insulintreated H-BMSCs. Our data revealed that insulin impeded osteogenesis of BMSCs by inhibiting autophagy and promoting premature senescence, which it should be responsible for T2DM-induced bone loss, at least in part. These findings suggest that inhibiting TGF-β1 pathway may be a potential therapeutic target for T2DM associated bone disorders.

Despite therapeutic advancements, there has been little improvement in the survival status of patients with oral squamous cell carcinoma (OSCC). HOX antisense intergenic RNA (HOTAIR) has been shown to be dysregulated in several cancer types. However, the roles of HOTAIR in OSCC remain largely unknown. In this study, we investigated the association of HOTAIR expression with clinicopathological features in OSCC patients and the crucial roles of HOTAIR in the modulation of tumor progression. Our results showed that HOTAIR was highly expressed both in OSCC tissue samples and cell lines compared with corresponding normal oral mucosa tissues and human oral keratinocytes. Its overexpression was positively correlated with TNM (tumor‐node‐metastases) stage, histological grade, and regional lymph node metastasis. The knockdown of HOTAIR by short hairpin RNA significantly decreased the migration, invasion, and epithelial‐mesenchymal transition of OSCC cells in vitro. Moreover, there was a negative correlation between HOTAIR and microRNA‐326 expression in OSCC tissue samples and cell lines. Luciferase reporter and loss‐of‐function assays revealed that HOTAIR acted as a competitive endogenous RNA effectively sponging miR‐326, thereby regulating the derepression of metastasis‐associated gene 2 (MTA2). Finally, the expression and clinical significance of MTA2 were analyzed in another cohort of OSCC tissue samples. High MTA2 expression was significantly correlated with clinicopathological features of advanced OSCC and poor prognosis for patients with OSCC. Collectively, HOTAIR overexpression promoted the progression of OSCC. The HOTAIR–miR‐326‐MTA2 axis may contribute to a better understanding of OSCC pathogenesis and be a potential therapeutic target for OSCC.

Craniofacial bone marrow mesenchymal stem cells (BMSCs) display some site-specific properties that differ from those of BMSCs derived from the trunk and appendicular skeleton, but the characteristics of craniofacial BMSCs and the mechanisms that underlie their properties are not completely understood. Previous studies indicated that special AT-rich binding protein 2 (SATB2) may be a potential regulator of craniofacial skeletal patterning and site-specific osteogenic capacity. Here, we investigated the stemness, autophagy, and anti-aging capacity of mandible-derived BMSCs (M-BMSCs) and tibia-derived BMSCs (T-BMSCs) and explored the role of SATB2 in regulating these properties. M-BMSCs not only possessed stronger expression of SATB2 and stemness markers (pluripotency genes, such as Nanog, OCT-4, Sox2, and Nestin) but also exhibited stronger autophagy and anti-aging capacities under normal or hypoxia/serum deprivation conditions compared to T-BMSCs. Exogenous expression of SATB2 in T-BMSCs significantly enhanced the expression of pluripotency genes as well as autophagy and anti-aging capacity. Moreover, SATB2 markedly enhanced osteogenic differentiation of BMSCs in vitro, and promoted bone defect regeneration and the survival of BMSCs that were transplanted into mandibles with critical size defects. Mechanistically, SATB2 upregulates pluripotency genes and autophagy-related genes, which in turn activate the mechanistic target of rapamycin signaling pathway. Collectively, our results provide novel evidence that site-specific BMSCs have distinct biological properties and suggest that SATB2 plays a potential role in regulating the stemness, autophagy, and anti-aging properties of craniofacial BMSCs. The application of SATB2 to manipulate stem cells for the reconstruction of bone defects might represent a new approach.