title: Altered ultrastructure, density and cathepsin K expression in bone of female muscarinic acetylcholine receptor M3 knockout mice.
abstract: High frequency of osteoporosis is found in postmenopausal women where several molecular components were identified to be involved in bone loss that subsequently leads to an increased fracture risk. Bone loss has already been determined in male mice with gene deficiency of muscarinic acetylcholine receptor M3 (M3R-KO). Here we asked whether bone properties of female 16-week old M3R-KO present similarities to osteoporotic bone loss by means of biomechanical, radiological, electron microscopic, cell- and molecular biological methods. Reduced biomechanical strength of M3R-KO correlated with cortical thickness and decreased bone mineral density (BMD). Femur and vertebrae of M3R-KO demonstrated a declined trabecular bone volume, surface, and a higher trabecular pattern factor and structure model index (SMI) compared to wild type (WT) mice. In M3R-KO, the number of osteoclasts as well as the cathepsin K mRNA expression was increased. Osteoclasts of M3R-KO showed an estimated increase in cytoplasmic vesicles. Further, histomorphometrical analysis revealed up-regulation of alkaline phosphatase. Osteoblasts and osteocytes showed a swollen cytoplasm with an estimated increase in the amount of rough endoplasmatic reticulum and in case of osteocytes a reduced pericellular space. Thus, current results on bone properties of 16-week old female M3R-KO are related to postmenopausal osteoporotic phenotype. Stimulation and up-regulation of muscarinic acetylcholine receptor subtype M3 expression in osteoblasts might be a possible new option for prevention and therapy of osteoporotic fractures. Pharmacological interventions and the risk of side effects have to be determined in upcoming studies.
authors.affiliation: Laboratory for Experimental Trauma Surgery, Justus-Liebig University Giessen, Kerkraderstr. 9, 35394 Giessen, Germany. Electronic address: Katrin.S.Lips@chiru.med.uni-giessen.de.
authors.forename: Katrin Susanne
authors.initials: KS
authors.lastname: Lips
authors.affiliation: Laboratory for Experimental Trauma Surgery, Justus-Liebig University Giessen, Kerkraderstr. 9, 35394 Giessen, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Kneffel
authors.affiliation: Laboratory for Experimental Trauma Surgery, Justus-Liebig University Giessen, Kerkraderstr. 9, 35394 Giessen, Germany.
authors.forename: Fee
authors.initials: F
authors.lastname: Willscheid
authors.affiliation: Department of Urology, University of Lübeck Medical School, Ratzeburger Allee 160, 23538 Lübeck, Germany.
authors.forename: Frank Martin
authors.initials: FM
authors.lastname: Mathies
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Hospital of Giessen-Marburg, Campus Giessen, Klinikstrasse 33, 35392 Giessen, Germany; Laboratory for Experimental Radiology, Justus-Liebig University Giessen, Schubertstr. 81, 35392 Giessen, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Kampschulte
authors.affiliation: Laboratory for Experimental Trauma Surgery, Justus-Liebig University Giessen, Kerkraderstr. 9, 35394 Giessen, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Laboratory for Experimental Trauma Surgery, Justus-Liebig University Giessen, Kerkraderstr. 9, 35394 Giessen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Panzer
authors.affiliation: Institute of Orthopaedic Research and Biomechanics, Center of Musculoskeletal Research University of Ulm, Ulm, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Dürselen
authors.affiliation: Laboratory for Experimental Trauma Surgery, Justus-Liebig University Giessen, Kerkraderstr. 9, 35394 Giessen, Germany; Department of Trauma Surgery Giessen, University Hospital of Giessen-Marburg, Campus Giessen, Rudolf-Buchheim-Str. 7, 35392 Giessen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Heiss
authors.affiliation: Laboratory for Experimental Trauma Surgery, Justus-Liebig University Giessen, Kerkraderstr. 9, 35394 Giessen, Germany.
authors.forename: Vivien
authors.initials: V
authors.lastname: Kauschke
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000502:physiology*; D001842:Bone and Bones / Q000378:metabolism / Q000648:ultrastructure*; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors
chemical_list: D043587:Receptor, Muscarinic M3; D056657:Cathepsin K
keywords: Biomechanics; Bone mineral density; Cholinergic receptor; Osteocyte; TRAP; Transmission electron microscopy