title: Adiponectin enhances osteogenic differentiation in human adipose-derived stem cells by activating the APPL1-AMPK signaling pathway.
abstract: Human adipose-derived stem cells (hASCs) are multipotent progenitor cells with multi-lineage differentiation potential including osteogenesis and adipogenesis. While significant progress has been made in understanding the transcriptional control of hASC fate, little is known about how hASC differentiation is regulated by the autocrine loop. The most abundant adipocytokine secreted by adipocytes, adiponectin (APN) plays a pivotal role in glucose metabolism and energy homeostasis. Growing evidence suggests a positive association between APN and bone formation yet little is known regarding the direct effects of APN on hASC osteogenesis. Therefore, this study was designed to investigate the varied osteogenic effects and regulatory mechanisms of APN in the osteogenic commitment of hASCs. We found that APN enhanced the expression of osteoblast-related genes in hASCs, such as osteocalcin, alkaline phosphatase, and runt-related transcription factor-2 (Runx2, also known as CBFa1), in a dose- and time-dependent manner. This was further confirmed by the higher expression levels of alkaline phosphatase and increased formation of mineralization nodules, along with the absence of inhibition of cell proliferation. Importantly, APN at 1 μg/ml was the optimal concentration, resulting in maximum deposition of calcium nodules, and was significant superior to bone morphogenetic protein 2. Mechanistically, we found for the first time that APN increased nuclear translocation of the leucine zipper motif (APPL)-1 as well as AMP-activated protein kinase (AMPK) phosphorylation, which were reversed by pretreatment with APPL1 siRNA. Our results indicate that APN promotes the osteogenic differentiation of hASCs by activating APPL1-AMPK signaling, suggesting that manipulation of APN is a novel therapeutic target for controlling hASC fate.
authors.affiliation: Second Dental Center, Peking University School and Hospital of Stomatology, Beijing, China; National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Chen
authors.affiliation: Second Dental Center, Peking University School and Hospital of Stomatology, Beijing, China; National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Wu
authors.affiliation: Second Dental Center, Peking University School and Hospital of Stomatology, Beijing, China; National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.affiliation: Second Dental Center, Peking University School and Hospital of Stomatology, Beijing, China; National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Second Dental Center, Peking University School and Hospital of Stomatology, Beijing, China; National Engineering Laboratory for Digital and Material Technology of Stomatology, Peking University School and Hospital of Stomatology, Beijing, China. Electronic address: tang_zhihui@live.cn.
authors.forename: Zhi-hui
authors.initials: ZH
authors.lastname: Tang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D052242:Adiponectin / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology*; D002454:Cell Differentiation; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006801:Humans; D010012:Osteogenesis; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
chemical_list: C464801:APPL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D052242:Adiponectin; D055372:AMP-Activated Protein Kinases
keywords: APPL1-AMPK signaling; Adiponectin; Adipose-derived stem cells; Bone tissue engineering; Osteogenic differentiation