title: Bone resorption in syndromes of the Ras/MAPK pathway.
abstract: Disorders of the Ras/mitogen-activated protein kinase (MAPK) pathway have an overlapping skeletal phenotype (e.g. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and neurofibromatosis type 1 (NF1) individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine-derived crosslinks of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Participants were individuals with Noonan syndrome (n = 14), Costello syndrome (n = 21), and cardiofaciocutaneous (CFC) syndrome (n = 14). Pyridinium crosslinks from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by high performance liquid chromatography. Three separate analyses of covariance were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. The Dpd and the Dpd/Pyd ratio were elevated (p < 0.0001) in all three conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.
authors.affiliation: Department of Pediatrics, University of Utah, Salt Lake City, UT 84132, USA. david.stevenson@hsc.utah.edu
authors.forename: D A
authors.initials: DA
authors.lastname: Stevenson
authors.forename: E L
authors.initials: EL
authors.lastname: Schwarz
authors.forename: J C
authors.initials: JC
authors.lastname: Carey
authors.forename: D H
authors.initials: DH
authors.lastname: Viskochil
authors.forename: H
authors.initials: H
authors.lastname: Hanson
authors.forename: S
authors.initials: S
authors.lastname: Bauer
authors.forename: H-Y Cindy
authors.initials: HY
authors.lastname: Weng
authors.forename: T
authors.initials: T
authors.lastname: Greene
authors.forename: K
authors.initials: K
authors.lastname: Reinker
authors.forename: J
authors.initials: J
authors.lastname: Swensen
authors.forename: R J
authors.initials: RJ
authors.lastname: Chan
authors.forename: F-C
authors.initials: FC
authors.lastname: Yang
authors.forename: L
authors.initials: L
authors.lastname: Senbanjo
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: R
authors.initials: R
authors.lastname: Mao
authors.forename: M
authors.initials: M
authors.lastname: Pasquali
mesh_terms: D015502:Absorptiometry, Photon; D000293:Adolescent; D000328:Adult; D000596:Amino Acids / Q000652:urine; D015415:Biomarkers / Q000652:urine; D015519:Bone Density; D001862:Bone Resorption / Q000235:genetics / Q000473:pathology* / Q000652:urine; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D015331:Cohort Studies; D003094:Collagen / Q000652:urine; D056685:Costello Syndrome / Q000235:genetics / Q000473:pathology / Q000652:urine; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000235:genetics / Q000473:pathology / Q000652:urine; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics / Q000473:pathology / Q000652:urine; D005260:Female; D005820:Genetic Testing; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology / Q000652:urine; D006801:Humans; D006868:Hydrolysis; D020935:MAP Kinase Signaling System; D008297:Male; D009634:Noonan Syndrome / Q000235:genetics / Q000473:pathology / Q000652:urine; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D000596:Amino Acids; D015415:Biomarkers; C015484:pyridinoline; C036020:deoxypyridinoline; D003094:Collagen; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)