title: Genetic determinants of fibro-osseous lesions in aged inbred mice.
abstract: Fibro-osseous lesions in mice are progressive aging changes in which the bone marrow is replaced to various degrees by fibrovascular stroma and bony trabeculae in a wide variety of bones. The frequency and severity varied greatly among 28 different inbred mouse stains, predominantly affecting females, ranging from 0% for 10 strains to 100% for KK/HlJ and NZW/LacJ female mice. Few lesions were observed in male mice and for 23 of the strains, no lesions were observed in males for any of the cohorts. There were no significant correlations between strain-specific severities of fibro-osseous lesions and ovarian (r=0.11; P=0.57) or endometrial (r=0.03; P=0.89) cyst formation frequency or abnormalities in parathyroid glands. Frequency of fibro-osseous lesions was most strongly associated (P<10(-6)) with genome variations on chromosome (Chr) 8 at 90.6 and 90.8Mb (rs33108071, rs33500669; P=5.0·10(-10), 1.3·10(-6)), Chr 15 at 23.6 and 23.8Mb (rs32087871, rs45770368; P=7.3·10(-7), 2.7·10(-6)), and Chr 19 at 33.2, 33.4, and 33.6Mb (rs311004232, rs30524929, rs30448815; P=2.8·10(-6), 2.8·10(-6), 2.8·10(-6)) in genome-wide association studies (GWAS). The relatively large number of candidate genes identified in the GWAS analyses suggests that this may be an extremely complex polygenic disease. These results indicate that fibro-osseous lesions are surprisingly common in many inbred strains of laboratory mice as they age. While this presents little problem in most studies that utilize young animals, it may complicate aging studies, particularly those focused on bone.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States. Electronic address: berndta@upmc.edu.
authors.forename: Annerose
authors.initials: A
authors.lastname: Berndt
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States. Electronic address: Cheryl_AckertBicknell@URMC.Rochester.edu.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Ackert-Bicknell
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States. Electronic address: kathleen.silva@jax.org.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Silva
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States. Electronic address: vicki.kennedy@jax.org.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Kennedy
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States. Electronic address: beth.sundberg@jax.org.
authors.forename: Beth A
authors.initials: BA
authors.lastname: Sundberg
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, United States. Electronic address: justin.m.cates@Vanderbilt.Edu.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom. Electronic address: PNS12@cam.ac.uk.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Schofield
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME, United States. Electronic address: john.sundberg@jax.org.
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
mesh_terms: D000375:Aging; D000818:Animals; D001847:Bone Diseases / Q000473:pathology*; D001853:Bone Marrow / Q000473:pathology*; D005260:Female; D005355:Fibrosis; D055106:Genome-Wide Association Study; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012376:Rodent Diseases / Q000235:genetics*; D012737:Sex Factors
keywords: Aging; Bone; Genome-wide association studies; KK/HlJ mice