title: Adiponectin regulates bone marrow mesenchymal stem cell niche through a unique signal transduction pathway: an approach for treating bone disease in diabetes.
abstract: Adiponectin (APN) is an adipocyte-secreted adipokine that exerts well-characterized antidiabetic properties. Patients with type 2 diabetes (T2D) are characterized by reduced APN levels in circulation and impaired stem cell and progenitor cell mobilization from the bone marrow for tissue repair and remodeling. In this study, we found that APN regulates the mobilization and recruitment of bone marrow-derived mesenchymal stem cells (BMSCs) to participate in tissue repair and regeneration. APN facilitated BMSCs migrating from the bone marrow into the circulation to regenerate bone by regulating stromal cell-derived factor (SDF)-1 in a mouse bone defect model. More importantly, we found that systemic APN infusion ameliorated diabetic mobilopathy of BMSCs, lowered glucose concentration, and promoted bone regeneration in diet-induced obesity mice. In vitro studies allowed us to identify Smad1/5/8 as a novel signaling mediator of APN receptor (AdipoR)-1 in BMSCs and osteoblasts. APN stimulation of MC3T3-E1 osteoblastic cells led to Smad1/5/8 phosphorylation and nuclear localization and increased SDF-1 mRNA expression. Although APN-mediated phosphorylation of Smad1/5/8 occurred independently from adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1, it correlated with the disassembly of protein kinase casein kinase 2 and AdipoR1 in immunoprecipitation experiments. Taken together, this study identified APN as a regulator of BMSCs migration in response to bone injury. Therefore, our findings suggest APN signaling could be a potential therapeutic target to improve bone regeneration and homeostasis, especially in obese and T2D patients.
authors.affiliation: Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Disease Center, Shanghai, China; Division of Oral Biology, Tufts University School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Yu
authors.forename: Qisheng
authors.initials: Q
authors.lastname: Tu
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Han
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Sui
authors.forename: Leilei
authors.initials: L
authors.lastname: Zheng
authors.forename: Shu
authors.initials: S
authors.lastname: Meng
authors.forename: Yin
authors.initials: Y
authors.lastname: Tang
authors.forename: Dongying
authors.initials: D
authors.lastname: Xuan
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.forename: Dana
authors.initials: D
authors.lastname: Murray
authors.forename: Qingping
authors.initials: Q
authors.lastname: Shen
authors.forename: Jessica
authors.initials: J
authors.lastname: Cheng
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
authors.forename: Lily Q
authors.initials: LQ
authors.lastname: Dong
authors.forename: Paloma
authors.initials: P
authors.lastname: Valverde
authors.forename: Xinming
authors.initials: X
authors.lastname: Cao
authors.forename: Jake
authors.initials: J
authors.lastname: Chen
mesh_terms: D016475:3T3 Cells; D052242:Adiponectin / Q000378:metabolism*; D000818:Animals; D001847:Bone Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D054377:Chemokine CXCL12 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D055153:Stem Cell Niche / Q000502:physiology*; D014162:Transfection
chemical_list: D052242:Adiponectin; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4
keywords: Adiponectin; Bone regeneration; Cell mobilization; Mesenchymal stem cells