title: Lack of prolidase causes a bone phenotype both in human and in mouse.
abstract: The degradation of the main fibrillar collagens, collagens I and II, is a crucial process for skeletal development. The most abundant dipeptides generated from the catabolism of collagens contain proline and hydroxyproline. In humans, prolidase is the only enzyme able to hydrolyze dipeptides containing these amino acids at their C-terminal end, thus being a key player in collagen synthesis and turnover. Mutations in the prolidase gene cause prolidase deficiency (PD), a rare recessive disorder. Here we describe 12 PD patients, 9 of whom were molecularly characterized in this study. Following a retrospective analysis of all of them a skeletal phenotype associated with short stature, hypertelorism, nose abnormalities, microcephaly, osteopenia and genu valgum, independent of both the type of mutation and the presence of the mutant protein was identified. In order to understand the molecular basis of the bone phenotype associated with PD, we analyzed a recently identified mouse model for the disease, the dark-like (dal) mutant. The dal/dal mice showed a short snout, they were smaller than controls, their femurs were significantly shorter and pQCT and μCT analyses of long bones revealed compromised bone properties at the cortical and at the trabecular level in both male and female animals. The differences were more pronounce at 1 month being the most parameters normalized by 2 months of age. A delay in the formation of the second ossification center was evident at postnatal day 10. Our work reveals that reduced bone growth was due to impaired chondrocyte proliferation and increased apoptosis rate in the proliferative zone associated with reduced hyperthrophic zone height. These data suggest that lack of prolidase, a cytosolic enzyme involved in the final stage of protein catabolism, is required for normal skeletogenesis especially at early age when the requirement for collagen synthesis and degradation is the highest.
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Besio
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Maruelli
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Gioia
authors.affiliation: Bone Metabolic Unit, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Villa
authors.affiliation: University of Sheffield, Sheffield, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Grabowski
authors.affiliation: University of Sheffield, Sheffield, UK.
authors.forename: Orla
authors.initials: O
authors.lastname: Gallagher
authors.affiliation: University of Sheffield, Sheffield, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Bishop
authors.affiliation: University of Sheffield, Sheffield, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Foster
authors.affiliation: Department of Drug Sciences, University of Pavia, Pavia, Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: De Lorenzi
authors.affiliation: Department of Drug Sciences, University of Pavia, Pavia, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Colombo
authors.affiliation: Pediatric Hematology and Oncology, Hospital Universitario Vall d'Hebron, Barcelona, Spain.
authors.forename: Josè Luis Dapena
authors.initials: JL
authors.lastname: Diaz
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Haether
authors.initials: H
authors.lastname: Moore-Barton
authors.affiliation: Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: Department of Pediatrics, Turgut Ozal University, Ankara, Turkey.
authors.forename: Halil Ibrahim
authors.initials: HI
authors.lastname: Aydin
authors.affiliation: Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Tokatli
authors.affiliation: Department of Dermatology, Medical University of Warsaw, Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Kwiek
authors.affiliation: Gazi University Hospital, Pediatric Metabolic Unit, Ankara, Turkey.
authors.forename: Cigdem Seher
authors.initials: CS
authors.lastname: Kasapkara
authors.affiliation: Gazi University Hospital, Pediatric Metabolic Unit, Ankara, Turkey.
authors.forename: Esra Ozsoy
authors.initials: EO
authors.lastname: Adisen
authors.affiliation: Gazi University Hospital, Pediatric Metabolic Unit, Ankara, Turkey.
authors.forename: Mehmet Ali
authors.initials: MA
authors.lastname: Gurer
authors.affiliation: Unit of Rare Diseases, Department of Pediatrics, Gaslini Institute, Genoa, Italy.
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.affiliation: Basic Research Laboratory, Center for Cancer Research, NCI at Frederick, Frederick, MD, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, USA.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Gunn
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Ruggero
authors.initials: R
authors.lastname: Tenni
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Department of Molecular Medicine, University of Pavia, Pavia, Italy. Electronic address: aforlino@unipv.it.
authors.forename: Antonella
authors.initials: A
authors.lastname: Forlino
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001483:Base Sequence; D049628:Body Size; D001842:Bone and Bones / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D003600:Cytosol / Q000201:enzymology; D004150:Dipeptidases / Q000378:metabolism*; D005260:Female; D005269:Femur / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000201:enzymology; D010641:Phenotype; D056732:Prolidase Deficiency / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012189:Retrospective Studies; D013977:Tibia / Q000473:pathology; D014057:Tomography, X-Ray Computed; D055114:X-Ray Microtomography; D055815:Young Adult
chemical_list: D004150:Dipeptidases; C022449:proline dipeptidase
keywords: Bone phenotype; Collagen; Growth plate; Prolidase; Prolidase deficiency