title: Impaired osteoclast homeostasis in the cystatin B-deficient mouse model of progressive myoclonus epilepsy.
abstract: Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is an autosomal recessively inherited disorder characterized by incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures with onset at the age of 6 to 16 years. EPM1 patients also exhibit a range of skeletal changes, e.g., thickened frontal cranial bone, arachnodactyly and scoliosis. Mutations in the gene encoding cystatin B (CSTB) underlie EPM1. CSTB is an inhibitor of cysteine cathepsins, including cathepsin K, a key enzyme in bone resorption by osteoclasts. CSTB has previously been shown to protect osteoclasts from experimentally induced apoptosis and to modulate bone resorption in vitro. Nevertheless, its physiological function in bone and the cause of the bone changes in patients remain unknown. Here we used the CSTB-deficient mouse (Cstb-/-) model of EPM1 to evaluate the contribution of defective CSTB protein function on bone pathology and osteoclast differentiation and function. Micro-computed tomography of hind limbs revealed thicker trabeculae and elevated bone mineral density in the trabecular bone ofCstb-/-mice. Histology fromCstb-/-mouse bones showed lower osteoclast count and thinner growth plates in long bones. Bone marrow-derived osteoclast cultures revealed lower osteoclast number and size in theCstb-/-group.Cstb-/-osteoclasts formed less and smaller resorption pits in an in vitro assay. This impaired resorptive capacity was likely due to a decrease in osteoclast numbers and size. These data imply that the skeletal changes inCstb-/-mice and in EPM1 patients are a result of CSTB deficiency leading to impaired osteoclast formation and consequently compromised resorptive capacity. These results suggest that the role of CSTB in osteoclast homeostasis and modulation of bone metabolism extends beyond cathepsin K regulation.
authors.affiliation: Folkhälsan Institute of Genetics, 00290 Helsinki, Finland; Research Program's Unit, Molecular Neurology, University of Helsinki, 00014 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Otto
authors.initials: O
authors.lastname: Manninen
authors.affiliation: Department of Medicine, University of Turku, 20520 Turku, Finland.
authors.forename: Tero
authors.initials: T
authors.lastname: Puolakkainen
authors.affiliation: Department of Medicine, University of Turku, 20520 Turku, Finland.
authors.forename: Jemina
authors.initials: J
authors.lastname: Lehto
authors.affiliation: Department of Anatomy, University of Turku, 20520 Turku, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Harittu
authors.affiliation: Department of Physics, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Aki
authors.initials: A
authors.lastname: Kallonen
authors.affiliation: Department of Physics, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Peura
authors.affiliation: Department of Anatomy, University of Turku, 20520 Turku, Finland.
authors.forename: Tiina
authors.initials: T
authors.lastname: Laitala-Leinonen
authors.affiliation: Folkhälsan Institute of Genetics, 00290 Helsinki, Finland; Research Program's Unit, Molecular Neurology, University of Helsinki, 00014 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Outi
authors.initials: O
authors.lastname: Kopra
authors.affiliation: Department of Physics, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Riku
authors.initials: R
authors.lastname: Kiviranta
authors.affiliation: Folkhälsan Institute of Genetics, 00290 Helsinki, Finland; Research Program's Unit, Molecular Neurology, University of Helsinki, 00014 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
keywords: CSTB, cystatin B; Cathepsin K,; Cystatin B,; EPM1, progressive myoclonus epilepsy of Unverricht–Lundborg type; Micro-computed tomography,; Osteoclast,; Osteogenesis,; Progressive myoclonus epilepsy; μCT, micro-computed tomography