title: An osteopontin-integrin interaction plays a critical role in directing adipogenesis and osteogenesis by mesenchymal stem cells.
abstract: An imbalance between normal adipogenesis and osteogenesis by mesenchymal stem cells (MSCs) has been shown to be related to various human metabolic diseases, such as obesity and osteoporosis; however, the underlying mechanisms remain elusive. We found that the interaction between osteopontin (OPN), an arginine-glycine-aspartate-containing glycoprotein, and integrin αv/β1 plays a critical role in the lineage determination of MSCs. Although OPN is a well-established marker during osteogenesis, its role in MSC differentiation is still unknown. Our study reveals that blockade of OPN function promoted robust adipogenic differentiation, while inhibiting osteogenic differentiation. Re-expression of OPN restored a normal balance between adipogenesis and osteogenesis in OPN(-/-) MSCs. Retarded bone formation by OPN(-/-) MSCs was also verified by in vivo implantation with hydroxyapatite-tricalcium phosphate, a bone-forming matrix. The role of extracellular OPN in MSC differentiation was further demonstrated by supplementation and neutralization of OPN. Blocking well-known OPN receptors integrin αv/β1 but not CD44 also affected MSC differentiation. Further studies revealed that OPN inhibits the C/EBPs signaling pathway through integrin αv/β1. Consistent with these in vitro results, OPN(-/-) mice had a higher fat to total body weight ratio than did wild-type mice. Therefore, our study demonstrates a novel role for OPN-integrin αv/β1 in regulating MSC differentiation.
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.forename: Peishun
authors.initials: P
authors.lastname: Shou
authors.forename: Liying
authors.initials: L
authors.lastname: Zhang
authors.forename: Chunliang
authors.initials: C
authors.lastname: Xu
authors.forename: Chunxing
authors.initials: C
authors.lastname: Zheng
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Han
authors.forename: Wenzhao
authors.initials: W
authors.lastname: Li
authors.forename: Yin
authors.initials: Y
authors.lastname: Huang
authors.forename: Xiaoren
authors.initials: X
authors.lastname: Zhang
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Roberts
authors.forename: Arnold B
authors.initials: AB
authors.lastname: Rabson
authors.forename: Guangwen
authors.initials: G
authors.lastname: Ren
authors.forename: Yanyun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: David T
authors.initials: DT
authors.lastname: Denhardt
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
mesh_terms: D017667:Adipocytes / Q000166:cytology; D050156:Adipogenesis / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage; D006801:Humans; D059630:Mesenchymal Stem Cells; D051379:Mice; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism*; D060066:Protein Interaction Maps / Q000235:genetics; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism*
chemical_list: D019030:Receptors, Vitronectin; C094340:integrin alphavbeta1; D053495:Osteopontin
keywords: Adipocytes; C/EBP; Differentiation; Integrins; Osteoblasts