Mannose 6-phosphate-dependent targeting of lysosomal enzymes is required for normal craniofacial and dental development
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Mannose 6-phosphate-dependent targeting of lysosomal enzymes is required for normal craniofacial and dental development. / Koehne, Till; Markmann, Sandra; Schweizer, Michaela; Muschol, Nicole; Friedrich, Reinhard E; Hagel, Christian; Glatzel, Markus; Kahl-Nieke, Bärbel; Amling, Michael; Schinke, Thorsten; Braulke, Thomas.
In: BBA-MOL BASIS DIS, Vol. 1862, No. 9, 09.2016, p. 1570–1580.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Mannose 6-phosphate-dependent targeting of lysosomal enzymes is required for normal craniofacial and dental development
AU - Koehne, Till
AU - Markmann, Sandra
AU - Schweizer, Michaela
AU - Muschol, Nicole
AU - Friedrich, Reinhard E
AU - Hagel, Christian
AU - Glatzel, Markus
AU - Kahl-Nieke, Bärbel
AU - Amling, Michael
AU - Schinke, Thorsten
AU - Braulke, Thomas
N1 - Copyright © 2016. Published by Elsevier B.V.
PY - 2016/9
Y1 - 2016/9
N2 - 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.
AB - 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.
U2 - 10.1016/j.bbadis.2016.05.018
DO - 10.1016/j.bbadis.2016.05.018
M3 - SCORING: Journal article
C2 - 27239697
VL - 1862
SP - 1570
EP - 1580
JO - BBA-MOL BASIS DIS
JF - BBA-MOL BASIS DIS
SN - 0925-4439
IS - 9
ER -
