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Bone resorption in syndromes of the Ras/MAPK pathway

D A Stevenson1, E L Schwarz, J C Carey

  • 1Department of Pediatrics, University of Utah, Salt Lake City, UT 84132, USA. david.stevenson@hsc.utah.edu

Clinical Genetics
|January 6, 2011
PubMed

Insights

Disorders affecting the Ras/mitogen-activated protein kinase (MAPK) pathway, including Noonan, Costello, and cardiofaciocutaneous syndromes, show increased bone resorption. This suggests the Ras/MAPK pathway is crucial for maintaining bone health.

Area of Science:

  • Genetics and Molecular Biology
  • Endocrinology and Metabolism
  • Skeletal Biology

Background:

  • Ras/mitogen-activated protein kinase (MAPK) pathway disorders are linked to skeletal abnormalities like scoliosis and osteopenia.
  • Neurofibromatosis type 1 (NF1) patients exhibit heightened osteoclast activity and bone resorption, indicated by elevated urinary pyridinium crosslinks.

Purpose of the Study:

  • To investigate whether other Ras/MAPK pathway syndromes also present with increased bone resorption.
  • To determine the impact of Ras/MAPK pathway dysregulation on skeletal phenotypes.

Main Methods:

  • Urine samples from individuals with Noonan syndrome (n=14), Costello syndrome (n=21), and cardiofaciocutaneous (CFC) syndrome (n=14) were analyzed.
  • Pyridinium crosslinks (pyridinoline [Pyd] and deoxypyridinoline [Dpd]) were extracted and quantified using high-performance liquid chromatography.
  • Statistical analyses (ANCOVA) compared crosslink levels between patient groups and 99 healthy controls, adjusting for age.

Main Results:

  • Deoxypyridinoline (Dpd) and the Dpd/Pyd ratio were significantly elevated in all three syndrome groups compared to controls (p < 0.0001).
  • The elevated Dpd levels suggest that collagen degradation primarily originates from bone tissue.

Conclusions:

  • The Ras/MAPK signal transduction pathway plays a significant role in regulating bone homeostasis.
  • Increased bone resorption is a common feature across multiple Ras/MAPK pathway-associated disorders, contributing to their skeletal phenotypes.

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