title: Sex-Linked Skeletal Phenotype of Lysyl Oxidase Like-1 Mutant Mice.
abstract: Lysyl oxidases are required for collagen and elastin cross-linking and extracellular matrix maturation including in bone. The lysyl oxidase family consists of lysyl oxidase (LOX) and 4 isoforms (LOXL1-4). Here we investigate whether deletion of LOXL1, which has been linked primarily to elastin maturation, leads to skeletal abnormalities. Left femurs (n = 8), L5 vertebrae (n = 8), and tibiae (n = 8) were analyzed by micro-computed tomography in 13-week-old wild-type (WT) and LOXL1-/- male and female mice. Right femurs (n = 8) were subjected to immunohistochemistry for LOXL1, and histochemical/histology analyses of osteoclasts and growth plates. Sera from all mice were analyzed for bone turnover markers. Results indicate strong expression of LOXL1 in wild-type growth plates in femurs. Significant deterioration of trabecular bone structure in long bones and vertebrae from female was observed but not from male, mutant mice compared with WT. Decreases in BV/TV, Conn.D, trabecular thickness, and number in the femoral distal metaphysis were observed in female, but not in male, mutant mice. Trabecular spacing was increased significantly in femurs of female mutant mice. Findings were similar in trabeculae of L5 vertebrae from female mutant mice. The number of TRAP positive osteoclasts at the trabecular bone surface was increased in female mutant mice compared with WT females, consistent with increased serum RANKL and decreased OPG levels. Analysis of bone turnover markers confirmed increased bone resorption as indicated by significantly elevated CTX-1 in the serum of female LOXL1-/- mice compared to their wild-type counterparts, as well as decreased bone formation as measured by decreased serum levels of PINP. Picrosirius red staining revealed a loss of heterogeneity in collagen organization in female LOXL1-/- mice only, with little to no yellow and orange birefringence. Organization was also impaired in chondrocyte columns in both female and male LOXL1-/- mice, but to a greater extent in females. Data indicate that LOXL1-/- mutant mice develop appendicular and axial skeletal phenotypes characterized by decreased bone volume fraction and compromised trabecular microstructure, predominantly in females.
authors.affiliation: Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, W-201, Boston, MA, 02118, USA.|Department of Endodontics, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Loai
authors.initials: L
authors.lastname: Alsofi
authors.affiliation: Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, W-201, Boston, MA, 02118, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Daley
authors.affiliation: Division of Dermatology, Washington University School of Medicine, Saint Louis, MO, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Hornstra
authors.affiliation: Department of Mechanical Engineering, Boston University, 110 Cummington Mall, Boston, MA, 02215, USA.
authors.forename: Elise F
authors.initials: EF
authors.lastname: Morgan
authors.affiliation: Department of Mechanical Engineering, Boston University, 110 Cummington Mall, Boston, MA, 02215, USA.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Mason
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: Jesus F
authors.initials: JF
authors.lastname: Acevedo
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
authors.forename: R Ann
authors.initials: RA
authors.lastname: Word
authors.affiliation: Department of Orthopaedic Surgery, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Louis C
authors.initials: LC
authors.lastname: Gerstenfeld
authors.affiliation: Department of Molecular and Cell Biology, Henry M. Goldman School of Dental Medicine, Boston University, 700 Albany Street, W-201, Boston, MA, 02118, USA. trackman@bu.edu.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Trackman
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D015519:Bone Density / Q000502:physiology; D001842:Bone and Bones / Q000000981:diagnostic imaging* / Q000378:metabolism; D005260:Female; D007118:Immunoassay; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D011857:Radiographic Image Interpretation, Computer-Assisted; D012727:Sex Characteristics; D055114:X-Ray Microtomography
chemical_list: D000594:Amino Acid Oxidoreductases; C482019:Loxl1 protein, mouse
keywords: Bone histomorphometry; Collagen; Genetic animal model; Lysyl oxidases; Micro-comuted tomography