title: Bone matrix, cellularity, and structural changes in a rat model with high-turnover osteoporosis induced by combined ovariectomy and a multiple-deficient diet.
abstract: In estrogen-deficient, postmenopausal women, vitamin D and calcium deficiency increase osteoporotic fracture risk. Therefore, a new rat model of combined ovariectomy and multiple-deficient diet was established to mimic human postmenopausal osteoporotic conditions under nutrient deficiency. Sprague-Dawley rats were untreated (control), laparatomized (sham), or ovariectomized and received a deficient diet (OVX-Diet). Multiple analyses involving structure (micro-computed tomography and biomechanics), cellularity (osteoblasts and osteoclasts), bone matrix (mRNA expression and IHC), and mineralization were investigated for a detailed characterization of osteoporosis. The study involved long-term observation up to 14 months (M14) after laparotomy or after OVX-Diet, with intermediate time points at M3 and M12. OVX-Diet rats showed enhanced osteoblastogenesis and osteoclastogenesis. Bone matrix markers (biglycan, COL1A1, tenascin C, and fibronectin) and low-density lipoprotein-5 (bone mass marker) were down-regulated at M12 in OVX-Diet rats. However, up-regulation of matrix markers and existence of unmineralized osteoid were seen at M3 and M14. Osteoclast markers (matrix metallopeptidase 9 and cathepsin K) were up-regulated at M14. Micro-computed tomography and biomechanics confirmed bone fragility of OVX-Diet rats, and quantitative RT-PCR revealed a higher turnover rate in the humerus than in lumbar vertebrae, suggesting enhanced bone formation and resorption in OVX-Diet rats. Such bone remodeling caused disturbed bone mineralization and severe bone loss, as reported in patients with high-turnover, postmenopausal osteoporosis. Therefore, this rat model may serve as a suitable tool to evaluate osteoporotic drugs and new biomaterials or fracture implants.
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany.
authors.forename: Parameswari
authors.initials: P
authors.lastname: Govindarajan
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany; Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Böcker
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany.
authors.forename: Thaqif
authors.initials: T
authors.lastname: El Khassawna
authors.affiliation: Department of Radiology, University Hospital of Giessen-Marburg, Giessen, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Kampschulte
authors.affiliation: Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen, Germany.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schlewitz
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Huerter
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany.
authors.forename: Ursula
authors.initials: U
authors.lastname: Sommer
authors.affiliation: Institute of Orthopaedic Research and Biomechanics, the Centre of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Dürselen
authors.affiliation: Institute of Orthopaedic Research and Biomechanics, the Centre of Musculoskeletal Research, University of Ulm, Ulm, Germany.
authors.forename: Anita
authors.initials: A
authors.lastname: Ignatius
authors.affiliation: Department of Veterinary Clinical Sciences, Clinical Pathology, and Clinical Pathophysiology, Justus-Liebig University, Giessen, Germany.
authors.forename: Natali
authors.initials: N
authors.lastname: Bauer
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany; Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen, Germany.
authors.forename: Gabor
authors.initials: G
authors.lastname: Szalay
authors.affiliation: Institute of Veterinary-Anatomy, Justus-Liebig University, Giessen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wenisch
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany.
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Lips
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany; Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schnettler
authors.affiliation: Department of Radiology, University Hospital of Giessen-Marburg, Giessen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Langheinrich
authors.affiliation: Laboratory of Experimental Trauma Surgery, Justus-Liebig University, Giessen, Germany; Department of Trauma Surgery, University Hospital of Giessen-Marburg, Giessen, Germany. Electronic address: christian.heiss@chiru.med.uni-giessen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Heiss
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000502:physiology; D001857:Bone Matrix / Q000166:cytology / Q000378:metabolism*; D016723:Bone Remodeling; D001862:Bone Resorption; D001842:Bone and Bones / Q000378:metabolism; D002113:Calcification, Physiologic; D003677:Deficiency Diseases / Q000150:complications*; D004032:Diet / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008159:Lumbar Vertebrae; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis; D015663:Osteoporosis, Postmenopausal / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D008077:Lipoproteins, LDL