title: Mannose 6-phosphate-dependent targeting of lysosomal enzymes is required for normal craniofacial and dental development.
abstract: Mucolipidosis II (MLII) is a severe systemic genetic disorder caused by defects in mannose 6-phosphate-dependent targeting of multiple lysosomal hydrolases and subsequent lysosomal accumulation of non-degraded material. MLII patients exhibit marked facial coarseness and gingival overgrowth soon after birth, accompanied with delayed tooth eruption and dental infections. To examine the pathomechanisms of early craniofacial and dental abnormalities, we analyzed mice with an MLII patient mutation that mimic the clinical and biochemical symptoms of MLII patients. The mouse data were compared with clinical and histological data of gingiva and teeth from MLII patients. Here, we report that progressive thickening and porosity of calvarial and mandibular bones, accompanied by elevated bone loss due to 2-fold higher number of osteoclasts cause the characteristic craniofacial phenotype in MLII. The analysis of postnatal tooth development by microcomputed tomography imaging and histology revealed normal dentin and enamel formation, and increased cementum thickness accompanied with accumulation of storage material in cementoblasts of MLII mice. Massive accumulation of storage material in subepithelial cells as well as disorganization of collagen fibrils led to gingival hypertrophy. Electron and immunofluorescence microscopy, together with (35)S-sulfate incorporation experiments revealed the accumulation of non-degraded material, non-esterified cholesterol and glycosaminoglycans in gingival fibroblasts, which was accompanied by missorting of various lysosomal proteins (α-fucosidase 1, cathepsin L and Z, Npc2, α-l-iduronidase). Our study shows that MLII mice closely mimic the craniofacial and dental phenotype of MLII patients and reveals the critical role of mannose 6-phosphate-dependent targeting of lysosomal proteins for alveolar bone, cementum and gingiva homeostasis.
authors.affiliation: Department of Orthodontics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Department of Osteology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Koehne
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Markmann
authors.affiliation: ZMNH, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Muschol
authors.affiliation: Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Reinhard E
authors.initials: RE
authors.lastname: Friedrich
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hagel
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: Department of Orthodontics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Kahl-Nieke
authors.affiliation: Department of Osteology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Department of Osteology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. Electronic address: braulke@uke.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
mesh_terms: D000818:Animals; D001846:Bone Development / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D005147:Facial Bones / Q000254:growth & development*; D005260:Female; D005881:Gingiva / Q000378:metabolism; D006801:Humans; D007223:Infant; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D008360:Mannosephosphates / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009081:Mucolipidoses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009805:Odontogenesis / Q000502:physiology*; D012886:Skull / Q000254:growth & development*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics
chemical_list: D008360:Mannosephosphates; C027693:mannose-6-phosphate; D017855:Transferases (Other Substituted Phosphate Groups); C511050:GNPTAB protein, human; C548056:GNPTAB protein, mouse; C504791:GNPTG protein, human
keywords: Cementoblasts; Craniofacial anomalies; Gingival hypertrophy; Lysosomes; Mucolipidosis II; Osteoclastogenesis