title: Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin.
abstract: Periostin (Postn) is a matricellular protein preferentially expressed by osteocytes and periosteal osteoblasts in response to mechanical stimulation and parathyroid hormone (PTH). Whether and how periostin expression influences bone anabolism, however, remains unknown. We investigated the skeletal response of adult Postn(-/-) and Postn(+/+) mice to intermittent PTH. Compared with Postn(+/+), Postn(-/-) mice had a lower bone mass, cortical bone volume, and strength response to PTH. PTH-stimulated bone-forming indices were all significantly lower in Postn(-/-) mice, particularly at the periosteum. Furthermore, in vivo stimulation of Wnt-β-catenin signaling by PTH, as evaluated in TOPGAL reporter mice, was inhibited in the absence of periostin (TOPGAL;Postn(-/-) mice). PTH stimulated periostin and inhibited MEF2C and sclerostin (Sost) expression in bone and osteoblasts in vitro. Recombinant periostin also suppressed Sost expression, which was mediated through the integrin αVβ3 receptor, whereas periostin-blocking antibody prevented inhibition of MEF2C and Sost by PTH. In turn, administration of a Sost-blocking antiboby partially restored the PTH-mediated increase in bone mass in Postn(-/-) mice. In addition, primary osteoblasts from Postn(-/-) mice showed a lower proliferation, mineralization, and migration, both spontaneously and in response to PTH. Osteoblastic gene expression levels confirmed a defect of Postn(-/-) osteoblast differentiation with and without PTH, as well as an increased osteoblast apoptosis in the absence of periostin. These data elucidate the complex role of periostin on bone anabolism, through the regulation of Sost, Wnt-β-catenin signaling, and osteoblast differentiation.
authors.affiliation: Division of Bone Diseases, Department of Rehabilitation and Geriatrics, World Health Organization Collaborating Center for Osteoporosis Prevention, Geneva University Hospital and Faculty of Medicine, Geneva 14, Switzerland. nicolas.bonnet@unige.ch
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bonnet
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Serge L
authors.initials: SL
authors.lastname: Ferrari
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D045930:Anabolic Agents / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006023:Glycoproteins / Q000378:metabolism; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; D051379:Mice; D018345:Mice, Knockout; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism*; D010521:Periosteum / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D055114:X-Ray Microtomography; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D045930:Anabolic Agents; D015815:Cell Adhesion Molecules; D006023:Glycoproteins; D039302:Integrin alphaVbeta3; D036341:Intercellular Signaling Peptides and Proteins; D064326:MEF2 Transcription Factors; C578041:Mef2c protein, mouse; D018006:Myogenic Regulatory Factors; D010281:Parathyroid Hormone; C082838:Postn protein, mouse; C486030:Sost protein, mouse; D051176:beta Catenin