Circular RNA circStag1 promotes bone regeneration by interacting with HuR

Postmenopausal osteoporosis is a common bone metabolic disorder characterized by deterioration of the bone microarchitecture,leading to an increased risk of fractures.Recently,circular RNAs(circ RNAs)have been demonstrated to play pivotal roles in regulating bone metabolism.However,the underlying functions of circ RNAs in bone metabolism in postmenopausal osteoporosis remain obscure.Here,we report that circ Stag1 is a critical osteoporosis-related circ RNA that shows significantly downregulated expression in osteoporotic bone marrow mesenchymal stem cells(BMSCs)and clinical bone tissue samples from patients with osteoporosis.Overexpression of circ Stag1 significantly promoted the osteogenic capability of BMSCs.Mechanistically,we found that circ Stag1 interacts with human antigen R(Hu R),an RNA-binding protein,and promotes the translocation of Hu R into the cytoplasm.A high cytoplasmic level of Hu R led to the activation of the Wnt signaling pathway by stabilizing and enhancing low-density lipoprotein receptor-related protein 5/6(Lrp5/6)andβ-catenin expression,thereby stimulating the osteogenic differentiation of BMSCs.Furthermore,overexpression of circ Stag1 in vivo by circ Stag1-loaded adeno-associated virus(circ Stag1-AAV)promoted new bone formation,thereby preventing bone loss in ovariectomized rats.Collectively,we show that circ Stag1 plays a pivotal role in promoting the regeneration of bone tissue via Hu R/Wnt signaling,which may provide new strategies to prevent bone metabolic disorders such as postmenopausal osteoporosis.

A novel sprayable thermosensitive hydrogel coupled with zinc modified metformin promotes the healing of skin wound

A novel sprayable adhesive is established(ZnMet-PF127)by the combination of a thermosensitive hydrogel(Pluronic F127,PF127)and a coordination complex of zinc and metformin(ZnMet).Here we demonstrate that ZnMet-PF127 potently promotes the healing of traumatic skin defect and burn skin injury by promoting cell proliferation,angiogenesis,collagen formation.Furthermore,we find that ZnMet could inhibit reactive oxygen species(ROS)production through activation of autophagy,thereby protecting cell from oxidative stress induced damage and promoting healing of skin wound.ZnMet complex exerts better effects on promoting skin wound healing than ZnCl2 or metformin alone.ZnMet complex also displays excellent antibacterial activity against Staphylococcus aureus or Escherichia coli,which could reduce the incidence of skin wound infections.Collectively,we demonstrate that sprayable PF127 could be used as a new drug delivery system for treatment of skin injury.The advantages of this sprayable system are obvious:(1)It is convenient to use;(2)The hydrogel can cover irregular skin defect sites evenly in a liquid state.In combination with this system,we establish a novel sprayable adhesive(ZnMet-PF127)and demonstrate that it is a potential clinical treatment for traumatic skin defect and burn skin injury.

Targeting Kindlin-2 in adipocytes increases bone mass through inhibiting FAS/PPARγ/FABP4 signaling in mice

Osteoporosis(OP)is a systemic skeletal disease that primarily affects the elderly population,which greatly increases the risk of fractures.Here we report that Kindlin-2 expression in adipose tissue increases during aging and high-fat diet fed and is accompanied by decreased bone mass.Kindlin-2 specific deletion(K2KO)controlled by Adipoq-Cre mice or adipose tissue-targeting AAV(AAV-Rec2-CasRx-sgK2)significantly increases bone mass.Mechanistically,Kindlin-2 promotes peroxisome proliferator-activated receptor gamma(PPARγ)activation and downstream fatty acid binding protein 4(FABP4)expression through stabilizing fatty acid synthase(FAS),and increased FABP4 inhibits insulin expression and decreases bone mass.Kindlin-2 inhibition results in accelerated FAS degradation,decreased PPARγactivation and FABP4 expression,and therefore increased insulin expression and bone mass.Interestingly,we find that FABP4 is increased while insulin is decreased in serum of OP patients.Increased FABP4 expression through PPARγactivation by rosiglitazone reverses the high bone mass phenotype of K2KO mice.Inhibition of FAS by C75 phenocopies the high bone mass phenotype of K2KO mice.Collectively,our study establishes a novel Kindlin-2/FAS/PPARγ/FABP4/insulin axis in adipose tissue modulating bone mass and strongly indicates that FAS and Kindlin-2 are new potential targets and C75 or AAV-Rec2-CasRx-sgK2 treatment are potential strategies for OP treatment.