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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.
PMID
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Authors

Mayor MeshTerms
Keywords

BONE METABOLISM

BONE MINERAL DENSITY

NBCCS

PTCH1

SPARC

Journal Title journal of bone and mineral research : the official journal of the american society for bone and mineral research
Publication Year Start
%A Hong, Yingying; Zhang, Jianyun; Zhang, Heyu; Li, Xuefen; Qu, Jiafei; Zhai, Jiemei; Zhang, Lei; Chen, Feng; Li, Tiejun
%T Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression.
%J Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, vol. 31, no. 7, pp. 1413-1428
%D 07/2016
%V 31
%N 7
%M eng
%B 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.
%P 1413
%L 1428
%Y 10.1002/jbmr.2815
%W PHY
%G AUTHOR
%R 2016JBMR...31.1413H

@Article{Hong2016,
author="Hong, Yingying
and Zhang, Jianyun
and Zhang, Heyu
and Li, Xuefen
and Qu, Jiafei
and Zhai, Jiemei
and Zhang, Lei
and Chen, Feng
and Li, Tiejun",
title="Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression.",
journal="Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
year="2016",
month="Jul",
day="12",
volume="31",
number="7",
pages="1413--1428",
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. {\textcopyright} 2016 American Society for Bone and Mineral Research.",
issn="1523-4681",
doi="10.1002/jbmr.2815",
url="http://www.ncbi.nlm.nih.gov/pubmed/26890308",
language="eng"
}

%0 Journal Article
%T Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression.
%A Hong, Yingying
%A Zhang, Jianyun
%A Zhang, Heyu
%A Li, Xuefen
%A Qu, Jiafei
%A Zhai, Jiemei
%A Zhang, Lei
%A Chen, Feng
%A Li, Tiejun
%J Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
%D 2016
%8 Jul 12
%V 31
%N 7
%@ 1523-4681
%G eng
%F Hong2016
%X 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.
%U http://dx.doi.org/10.1002/jbmr.2815
%U http://www.ncbi.nlm.nih.gov/pubmed/26890308
%P 1413-1428

PT Journal
AU Hong, Y
   Zhang, J
   Zhang, H
   Li, X
   Qu, J
   Zhai, J
   Zhang, L
   Chen, F
   Li, T
TI Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression.
SO Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
JI J. Bone Miner. Res.
PD Jul
PY 2016
BP 1413
EP 1428
VL 31
IS 7
DI 10.1002/jbmr.2815
LA eng
AB 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.
ER

PMID- 26890308
OWN - NLM
STAT- In-Data-Review
DA  - 20160705
IS  - 1523-4681 (Electronic)
IS  - 0884-0431 (Linking)
VI  - 31
IP  - 7
DP  - 2016 Jul
TI  - Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid
      Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression.
PG  - 1413-28
LID - 10.1002/jbmr.2815 [doi]
AB  - 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. (c) 2016 American Society for Bone and 
      Mineral Research.
CI  - (c) 2016 American Society for Bone and Mineral Research.
FAU - Hong, Yingying
AU  - Hong Y
AD  - Department of Oral Pathology, Peking University School and Hospital of
      Stomatology, Beijing, China.
FAU - Zhang, Jianyun
AU  - Zhang J
AD  - Department of Oral Pathology, Peking University School and Hospital of
      Stomatology, Beijing, China.
FAU - Zhang, Heyu
AU  - Zhang H
AD  - Central Laboratory, Peking University School and Hospital of Stomatology,
      Beijing, China.
FAU - Li, Xuefen
AU  - Li X
AD  - Central Laboratory, Peking University School and Hospital of Stomatology,
      Beijing, China.
FAU - Qu, Jiafei
AU  - Qu J
AD  - Department of Oral Pathology, Peking University School and Hospital of
      Stomatology, Beijing, China.
FAU - Zhai, Jiemei
AU  - Zhai J
AD  - Department of Oral Pathology, Peking University School and Hospital of
      Stomatology, Beijing, China.
FAU - Zhang, Lei
AU  - Zhang L
AD  - Department of Oral Maxillofacial Surgery, Peking University School and Hospital
      of Stomatology, Beijing, China.
FAU - Chen, Feng
AU  - Chen F
AD  - Central Laboratory, Peking University School and Hospital of Stomatology,
      Beijing, China.
FAU - Li, Tiejun
AU  - Li T
AD  - Department of Oral Pathology, Peking University School and Hospital of
      Stomatology, Beijing, China.
LA  - eng
PT  - Journal Article
DEP - 20160312
PL  - United States
TA  - J Bone Miner Res
JT  - Journal of bone and mineral research : the official journal of the American
      Society for Bone and Mineral Research
JID - 8610640
SB  - IM
OTO - NOTNLM
OT  - BONE METABOLISM
OT  - BONE MINERAL DENSITY
OT  - NBCCS
OT  - PTCH1
OT  - SPARC
EDAT- 2016/02/19 06:00
MHDA- 2016/02/19 06:00
CRDT- 2016/02/19 06:00
PHST- 2015/10/24 [received]
PHST- 2016/01/23 [revised]
PHST- 2016/02/13 [accepted]
PHST- 2016/03/12 [aheadofprint]
AID - 10.1002/jbmr.2815 [doi]
PST - ppublish
SO  - J Bone Miner Res. 2016 Jul;31(7):1413-28. doi: 10.1002/jbmr.2815. Epub 2016 Mar
      12.
TY  - JOUR
AU  - Hong, Yingying
AU  - Zhang, Jianyun
AU  - Zhang, Heyu
AU  - Li, Xuefen
AU  - Qu, Jiafei
AU  - Zhai, Jiemei
AU  - Zhang, Lei
AU  - Chen, Feng
AU  - Li, Tiejun
PY  - 2016/Jul/12
TI  - Heterozygous PTCH1 Mutations Impact the Bone Metabolism in Patients With Nevoid Basal Cell Carcinoma Syndrome Likely by Regulating SPARC Expression.
T2  - J. Bone Miner. Res.
JO  - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
SP  - 1413
EP  - 1428
VL  - 31
IS  - 7
N2  - 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.
SN  - 1523-4681
UR  - http://dx.doi.org/10.1002/jbmr.2815
UR  - http://www.ncbi.nlm.nih.gov/pubmed/26890308
ID  - Hong2016
ER  - 
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<b:Comments>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. &#169; 2016 American Society for Bone and Mineral Research.</b:Comments>
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