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.