No abstract

Emerging evidence has indicated that estrogen deficiency contributes to osteoporosis by affecting the level of inflammation. The inflammation microenvironment affects many cellular physiological processes, one of which may be cellular senescence according to previous studies. Senescent cells cannot function normally and secrete inflammatory cytokines and degradative proteins, which are referred to as senescence-associated secretory phenotype (SASP) factors, inducing further senescence and inflammation. Thus, stopping this vicious cycle may be helpful for postmenopausal osteoporosis treatment. Here, we used ovariectomized (OVX) mice as an estrogen-deficient model and confirmed that OVX bone marrow mesenchymal stem cells (BMSCs) displayed a senescent phenotype and upregulated SASP factor secretion both in vitro and in vivo. Furthermore, JAK2/STAT3, an important cytokine secretion-related signalling pathway that is associated with SASP secretion, was activated. Estrogen addition and estrogen receptor blockade confirmed that the JAK2/STAT3 axis participated in OVX BMSC senescence by mediating SASP factors. And JAK inhibition reduced SASP factor expression, alleviated senescence and enhanced osteogenic differentiation. Intraperitoneal injection of a JAK inhibitor, ruxolitinib, prevented bone loss in OVX mice. Collectively, our results revealed that JAK2/STAT3 plays an important role in the inflammation-senescence-SASP feedback loop in OVX BMSCs and that JAK inhibition could be a new method for treating postmenopausal osteoporosis.

Osteoporosis is a complex and multifactorial disease caused by an imbalance between bone formation and resorption. Post-menopausal women with endogenous estrogen deficiency suffer from systemic bone loss and osteoporosis, and are at high risk of this affecting the jaw bones. MicroRNAs (miRNAs or miRs) have been implicated in the mechanisms of metabolic bone diseases and are expressed at differential levels in alveolar bone following ovariectomy. In the present study, we systematically analyzed the expression profiles of miRNAs, mRNAs and long non-coding RNA (lncRNAs) in the mandible of ovariectomized (OVX) mice. A complex miRNA-mRNA-lncRNA regulatory network was constructed based on differentially expressed RNAs. Two core differentially expressed genes (DEGs), namely, LRP2 binding protein (Lrp2bp) and perilipin 4 (Plin4), significantly influenced the network targeted by differentially expressed miRNAs. Moreover, peroxisome proliferator-activated receptor (PPAR) and insulin signaling pathways were significantly dysregulated in the mandible of OVX mice. Several differentially expressed lncRNAs were also implicated in the two signaling pathways, which influenced mandible development by forming competing endogenous RNA. On the whole, our data indicate that the comprehensive analysis of miRNAs, mRNAs and lncRNAs provides insight into the pathogenesis of estrogen deficiency-induced osteoporosis in the mandible. This study proposes potential biomarkers for diagnosis or therapeutic targets for osteoporosis which may aid in the development of novel drugs for the treatment of osteoporosis.