Bone growth and remodeling is inhibited by denervation in adults and children, resulting in alterations of linear growth and bone mass and increased risk for osteoporosis and pathologic fractures. Transforming growth factor beta (TGF-β) isoforms are a key group of growth factors that enhance bone formation. To explore the relation between denervation-induced reduction of bone formation and TGF-β gene expression, we measured mRNA levels of TGF-β in denervation mouse bone and found decreased mRNA levels of TGF-β1, TGF-β2 and TGF-β3. These changes were accompanied by diminishing weight loss, bone mineral density (BMD), trabecular thickness, trabecular separation and trabecular number of femur and lumbar, serum osteocalcin, total calcium, intact parathyroid hormone, and increased serum C telopeptide. Recombinant human TGF-β1 (rhTGF-β1) prevented denervation-induced reduction of BMD further supporting our hypothesis that denervation-induced reduction of bone formation is a result of inhibition of TGF-β gene expression. In addition, antiprogestins RU 38486 blunted the denervation-induced decrease in mRNA levels of TGF-β group, while dexamethasone (DEX) decreased TGF-β group mRNA levels in normal mice. Furthermore, the denervated-mice exhibited a threefold increase in plasma corticosterone. These results suggest that denervation-induced reduction of bone formation may be regulated by glucocorticoids via inhibition of TGF-β gene expression at least in part.

Autophagy plays critical roles in the pluripotent stemness of cancer stem cells (CSCs). However, how CSCs maintain the elevated autophagy to support stemness remains elusive. Here, we demonstrate that bladder cancer stem-like cells (BCSLCs) are at slow-cycling state with enhanced autophagy and mitophagy. In these slow-cycling BCSLCs, the DNA replication initiator MCM7 is required for autophagy and stemness. MCM7 knockdown inhibits autophagic flux and reduces the stemness of BCSLCs. MCM7 can facilitate autolysosome formation through binding with dynein to promote autophagic flux. The enhanced autophagy/mitophagy helps BCSLCs to maintain mitochondrial respiration, thus inhibiting AMPK activation. AMPK activation can trigger switch from autophagy to apoptosis, through increasing BCL2/BECLIN1 interaction and inducing P53 accumulation. In summary, we find that MCM7 can promote autophagic flux to support.

Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the pathogenesis and progression of rheumatoid arthritis (RA). It is urgent to develop new drugs that can effectively inhibit the abnormal activation of RA-FLS. In our study, the RA-FLS cell line, MH7A, and mice with collagen-induced arthritis (CIA) were used to evaluate the effect of paclitaxel (PTX). Based on the results, PTX inhibited the migration of RA-FLS in a dose-dependent manner and significantly reduced the spontaneous expression of IL-6, IL-8, and RANKL mRNA and TNF-α-induced transcription of the IL-1β, IL-8, MMP-8, and MMP-9 genes. However, PTX had no significant effect on apoptosis in RA-FLS. Mechanistic studies revealed that PTX significantly inhibited the TNF-α-induced phosphorylation of ERK1/2 and JNK in the mitogen-activated protein kinase (MAPK) pathway and suppressed the TNF-α-induced activation of AKT, p70S6K, 4EBP1, and HIF-1α in the AKT/mTOR pathway. Moreover, PTX alleviated synovitis and bone destruction in CIA mice. In conclusion, PTX inhibits the migration and inflammatory mediator production of RA-FLS by targeting the MAPK and AKT/mTOR signaling pathways, which provides an experimental basis for the potential application in the treatment of RA.