Lack of prolidase causes a bone phenotype both in human and in mouse

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dc.authoridtokatli, aysegul/0000-0003-2812-9319|Grabowski, Peter/0000-0001-5924-1587|Colombo, Raffaella/0000-0001-9675-6598|Dapena Diaz, Jose Luis/0000-0002-6711-7479|De Lorenzi, Ersilia/0000-0002-5450-7208|AYDIN, Halil Ibrahim/0000-0001-7994-4394|Besio, Roberta/0000-0003-1430-2934|Gunn, Teresa/0000-0003-2688-6420|Kasapkara, Cigdem/0000-0002-3569-276X|Kwiek, Bartlomiej/0000-0002-0090-8444;
dc.contributor.authorBesio, Roberta
dc.contributor.authorMaruelli, Silvia
dc.contributor.authorGioia, Roberta
dc.contributor.authorVilla, Isabella
dc.contributor.authorGrabowski, Peter
dc.contributor.authorGallagher, Orla
dc.contributor.authorBishop, Nicholas J.
dc.date.accessioned2025-10-24T18:08:58Z
dc.date.available2025-10-24T18:08:58Z
dc.date.issued2015
dc.departmentMalatya Turgut Özal Üniversitesi
dc.description.abstractThe 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 mu CT 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. (C) 2014 Elsevier Inc. All rights reserved.
dc.description.sponsorshipFONDAZIONE CARIPLO [2013-0612, 2011-0270]; European Community [602300]
dc.description.sponsorshipThe authors wish to acknowledge Mr Angelo Gallanti, Department of Molecular Medicine, Biochemistry Unit, University of Pavia, Pavia, Italy, for the tissue culture support and Dr Alessandro Rubinacci, MD, Head of the Bone Metabolic Unit, San Raffaele Scientific Institute, Milan, Italy, for the helpful discussion of the data. This work was supported by FONDAZIONE CARIPLO 2013-0612 to A.F., the European Community's Seventh Framework Programme under grant agreement n. 602300 (SYBIL) to A.R. and A.F. and FONDAZIONE CARIPLO 2011-0270 to R.T.
dc.identifier.doi10.1016/j.bone.2014.11.009
dc.identifier.endpage64
dc.identifier.issn8756-3282
dc.identifier.issn1873-2763
dc.identifier.pmid25460580
dc.identifier.scopus2-s2.0-84913593588
dc.identifier.scopusqualityQ1
dc.identifier.startpage53
dc.identifier.urihttps://doi.org/10.1016/j.bone.2014.11.009
dc.identifier.urihttps://hdl.handle.net/20.500.12899/3391
dc.identifier.volume72
dc.identifier.wosWOS:000348007900007
dc.identifier.wosqualityQ2
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoen
dc.publisherElsevier Science Inc
dc.relation.ispartofBone
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/closedAccess
dc.snmzKA_20251023
dc.subjectProlidase; Prolidase deficiency; Bone phenotype; Growth plate; Collagen
dc.titleLack of prolidase causes a bone phenotype both in human and in mouse
dc.typeArticle

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