title: Phenotypic characterization of Grm1crv4mice reveals a functional role for the type 1 metabotropic glutamate receptor in bone mineralization.
abstract: Recent increasing evidence supports a role for neuronal type signaling in bone. Specifically glutamate receptors have been found in cells responsible for bone remodeling, namely the osteoblasts and the osteoclasts. While most studies have focused on ionotropic glutamate receptors, the relevance of the metabotropic glutamate signaling in bone is poorly understood. Specifically type 1 metabotropic glutamate (mGlu1) receptors are expressed in bone, but the effect of its ablation on skeletal development has never been investigated. Here we report that Grm1crv4/crv4mice, homozygous for an inactivating mutation of the mGlu1 receptor, and mainly characterized by ataxia and renal dysfunction, exhibit decreased body weight, bone length and bone mineral density compared to wild type (WT) animals. Blood analyses of the affected mice demonstrate the absence of changes in circulating factors, such as vitamin D and PTH, suggesting renal damage is not the main culprit of the skeletal phenotype. Cultures of osteoblasts lacking functional mGlu1 receptors exhibit less homogeneous collagen deposition than WT cells, and present increased expression of osteocalcin, a marker of osteoblast maturation. These data suggest that the skeletal damage is directly linked to the absence of the receptor, which in turn leads to osteoblasts dysfunction and earlier maturation. Accordingly, skeletal histomorphology suggests that Grm1crv4/crv4mice exhibit enhanced bone maturation, resulting in premature fusion of the growth plate and shortened long bones, and further slowdown of bone apposition rate compared to the WT animals. In summary, this work reveals novel functions of mGlu1 receptors in the bone and indicates that in osteoblasts mGlu1 receptors are necessary for production of normal bone matrix, longitudinal bone growth, and normal skeletal development.
authors.affiliation: DiNOGMI, University of Genoa, via Gaslini 5, 16148 Genoa, Italy. Electronic address: Ilaria.musante@unige.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Musante
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico, via Pace 9, 20122 Milan, Italy; Fondazione D'Amico per la Ricerca sulle Malattie Renali, via Pace 9, 20122 Milan, Italy. Electronic address: deborah.mattinzoli@gmail.com.
authors.forename: Deborah
authors.initials: D
authors.lastname: Mattinzoli
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom. Electronic address: lao1e13@soton.ac.uk.
authors.forename: Lavinia Alexandra
authors.initials: LA
authors.lastname: Otescu
authors.affiliation: DiNOGMI, University of Genoa, via Gaslini 5, 16148 Genoa, Italy. Electronic address: 3041842@studenti.unige.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Bossi
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico, via Pace 9, 20122 Milan, Italy; Fondazione D'Amico per la Ricerca sulle Malattie Renali, via Pace 9, 20122 Milan, Italy. Electronic address: masami.ikehata@gmail.com.
authors.forename: Masami
authors.initials: M
authors.lastname: Ikehata
authors.affiliation: Laboratory of Regenerative Medicine, DIMES, IRCCS AOU San Martino-IST, Largo Rosanna Benzi 10, University of Genova, Genova, Italy. Electronic address: chiara.gentili@unige.it.
authors.forename: Chiara
authors.initials: C
authors.lastname: Gentili
authors.affiliation: Clinical Pathology Laboratory Unit, Istituto Giannina Gaslini, via Gaslini 5, 16148 Genoa, Italy. Electronic address: GiulianaCangemi@ospedale-gaslini.ge.it.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cangemi
authors.affiliation: Clinical Pathology Laboratory Unit, Istituto Giannina Gaslini, via Gaslini 5, 16148 Genoa, Italy. Electronic address: cinzia.dy@gmail.com.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Gatti
authors.affiliation: Animal Facility, IRCCS A.U.O. San Martino-IST, Largo Rosanna Benzi 10, Genoa, Italy. Electronic address: laura.emionite@hsanmartino.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Emionite
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico, via Pace 9, 20122 Milan, Italy; Fondazione D'Amico per la Ricerca sulle Malattie Renali, via Pace 9, 20122 Milan, Italy. Electronic address: pmessa@policlinico.mi.it.
authors.forename: Piergiorgio
authors.initials: P
authors.lastname: Messa
authors.affiliation: DiNOGMI, University of Genoa, via Gaslini 5, 16148 Genoa, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, via Gaslini 5, 16148 Genoa, Italy. Electronic address: rravazzo@unige.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.affiliation: Renal Research Laboratory, Fondazione IRCCS Ospedale Maggiore Policlinico, via Pace 9, 20122 Milan, Italy; Fondazione D'Amico per la Ricerca sulle Malattie Renali, via Pace 9, 20122 Milan, Italy. Electronic address: mariapia.rastaldi@policlinico.mi.it.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Rastaldi
authors.affiliation: School of Biosciences, Cardiff University, Cardiff, United Kingdom. Electronic address: Riccardi@cardiff.ac.uk.
authors.forename: Daniela
authors.initials: D
authors.lastname: Riccardi
authors.affiliation: DiNOGMI, University of Genoa, via Gaslini 5, 16148 Genoa, Italy; Medical Genetics Unit, Istituto Giannina Gaslini, via Gaslini 5, 16148 Genoa, Italy. Electronic address: apuliti@unige.it.
authors.forename: Aldamaria
authors.initials: A
authors.lastname: Puliti
mesh_terms: D000818:Animals; D049628:Body Size; D015519:Bone Density; D001846:Bone Development; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D005260:Female; D008297:Male; D008807:Mice, Inbred BALB C; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010641:Phenotype; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1
keywords: Ataxia; Bone mineralization; Grm1(crv4) mouse; Osteoblasts; Skeletal defect; mGlu1 receptor