Connective tissue alterations in Fkbp10-/- mice.
Osteogenesis imperfecta (OI) is an inherited brittle bone disorder characterized by bone fragility and low bone mass. Loss of function mutations in FK506-binding protein 10 (FKBP10), encoding the FKBP65 protein, result in recessive OI and Bruck syndrome, of which the latter is additionally characterized by joint contractures. FKBP65 is thought to act as a collagen chaperone, but it is unknown how loss of FKBP65 affects collagen synthesis and extracellular matrix formation. We evaluated the developmental and postnatal expression of Fkbp10 and analyzed the consequences of its generalized loss of function. Fkbp10 is expressed at low levels in E13.5 mouse embryos, particularly in skeletal tissues, and steadily increases through E17.5 with expression in not only skeletal tissues, but also in visceral tissues. Postnatally, expression is limited to developing bone and ligaments. In contrast to humans, with complete loss of function mutations, Fkbp10(-/-) mice do not survive birth, and embryos present with growth delay and tissue fragility. Type I calvarial collagen isolated from these mice showed reduced stable crosslink formation at telopeptide lysines. Furthermore, Fkbp10(-/-) mouse embryonic fibroblasts show retention of procollagen in the cell layer and associated dilated endoplasmic reticulum. These data suggest a requirement for FKBP65 function during embryonic connective tissue development in mice, but the restricted expression postnatally in bone, ligaments and tendons correlates with the bone fragility and contracture phenotype in humans.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Caressa D
CD
Lietman
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Abbhirami
A
Rajagopal
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Erica P
EP
Homan
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Elda
E
Munivez
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Howard Hughes Medical Institute, Houston, TX 77030, USA.
Ming-Ming
MM
Jiang
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Terry K
TK
Bertin
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Howard Hughes Medical Institute, Houston, TX 77030, USA.
Yuqing
Y
Chen
Department of Pathology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA.
John
J
Hicks
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, USA.
MaryAnn
M
Weis
Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA 98195, USA.
David
D
Eyre
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA Howard Hughes Medical Institute, Houston, TX 77030, USA, blee@bcm.edu.
Brendan
B
Lee
Department of Orthopaedic Surgery and Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA.
Deborah
D
Krakow
D000818:Animals; D000831:Animals, Newborn; D001842:Bone and Bones / Q000378:metabolism; D003238:Connective Tissue / Q000196:embryology / Q000502:physiology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005804:Genes, Lethal; D006801:Humans; D008022:Ligaments / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010013:Osteogenesis Imperfecta / Q000235:genetics* / Q000473:pathology*; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D013710:Tendons / Q000378:metabolism
D022021:Tacrolimus Binding Proteins; C491675:Fkbp10 protein, mouse