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2330878 
Journal Article 
Bone resorption in syndromes of the Ras/MAPK pathway 
Stevenson, DA; Schwarz, EL; Carey, JC; Viskochil, DH; Hanson, H; Bauer, S; Weng, HYC; Greene, T; Reinker, K; Swensen, J; Chan, RJ; Yang, FC; Senbanjo, L; Yang, Z; Mao, R; Pasquali, M 
2011 
Yes 
Clinical Genetics
ISSN: 0009-9163
EISSN: 1399-0004 
80 
6 
566-573 
English 
21204800 
WOS:000296915000010 
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. 
bone; cardiofaciocutaneous syndrome; Costello syndrome; Noonan syndrome; pyridinium