title: Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression.
abstract: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder characterized by bone and skin abnormalities and a predisposition to various tumors. Keratocystic odontogenic tumors (KCOTs), which are common tumors of the jaw that cause extensive damage to the jawbone, are usually accompanied with NBCCS. Germline PTCH1 mutations in NBCCS tumorigenesis have been frequently studied; however, little is known regarding the pathogenesis of bone abnormalities in this disease. This study sought to investigate the mechanism underlying heterozygous PTCH1 mutation-mediated abnormal bone metabolism in patients with NBCCS. Stromal cells were isolated from the fibrous capsules of patients with NBCCS-associated or non-syndromic keratocystic odontogenic tumors and non-syndromic tumor stromal cells without PTCH1 mutations served as controls. Germline PTCH1 heterozygous mutations were confirmed in all NBCCS samples and differential protein expression was identified using tandem mass tag-labeled proteomics analysis. Our findings revealed that osteonectin/SPARC expression was significantly downregulated in syndromic stromal cells compared with non-syndromic stromal cells. SPARC expression was even lower in stromal cells carrying PTCH1 protein truncation mutations. PTCH1 siRNA transfection demonstrated that SPARC downregulation correlates with decreased PTCH1 expression. Furthermore, exogenous SPARC promoted osteogenic differentiation of syndromic stromal cells with enhanced development of calcium nodules. In addition, bone mineral density tests showed that patients with NBCCS exhibit weak bone mass compared with sex- and age-matched controls. This study indicates that germline PTCH1 heterozygous mutations play a major role in bone metabolism in patients with NBCCS, in particular in those with PTCH1 protein truncation mutations. SPARC may represent an important downstream modulator of PTCH1 mediation of bone metabolism. Thus, bone mineral density monitoring is critical for patients with NBCCS for prevention of osteoporosis. In addition, surgical procedures on syndromic-associated KCOTs should be performed with consideration of the weaker bone mass in such patients. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Heyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Xuefen
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Jiafei
authors.initials: J
authors.lastname: Qu
authors.affiliation: Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Jiemei
authors.initials: J
authors.lastname: Zhai
authors.affiliation: Department of Oral Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China.
authors.forename: Tiejun
authors.initials: T
authors.lastname: Li
mesh_terms: D001478:Basal Cell Nevus Syndrome / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D008297:Male; D015676:Osteonectin / Q000096:biosynthesis* / Q000235:genetics; D000072081:Patched-1 Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D015676:Osteonectin; C000606236:PTCH1 protein, human; D000072081:Patched-1 Receptor; C577241:SPARC protein, human
keywords: BONE METABOLISM; BONE MINERAL DENSITY; NBCCS; PTCH1; SPARC