title: Chemical and biomechanical characterization of hyperhomocysteinemic bone disease in an animal model.
abstract: BACKGROUND
  Classical homocystinuria is an autosomal recessive disorder caused by cystathionine beta-synthase (CBS) deficiency and characterized by distinctive alterations of bone growth and skeletal development. Skeletal changes include a reduction in bone density, making it a potentially attractive model for the study of idiopathic osteoporosis.
  
  
  METHODS
  To investigate this aspect of hyperhomocysteinemia, we supplemented developing chicks (n = 8) with 0.6% dl-homocysteine (hCySH) for the first 8 weeks of life in comparison to controls (n = 10), and studied biochemical, biomechanical and morphologic effects of this nutritional intervention.
  
  
  RESULTS
  hCySH-fed animals grew faster and had longer tibiae at the end of the study. Plasma levels of hCySH, methionine, cystathionine, and inorganic sulfate were higher, but calcium, phosphate, and other indices of osteoblast metabolism were not different. Radiographs of the lower limbs showed generalized osteopenia and accelerated epiphyseal ossification with distinct metaphyseal and suprametaphyseal lucencies similar to those found in human homocystinurics. Although biomechanical testing of the tibiae, including maximal load to failure and bone stiffness, indicated stronger bone, strength was proportional to the increased length and cortical thickness in the hCySH-supplemented group. Bone ash weights and IR-spectroscopy of cortical bone showed no difference in mineral content, but there were higher Ca2+/PO4(3-) and lower Ca2+/CO3(2-) molar ratios than in controls. Mineral crystallization was unchanged.
  
  
  CONCLUSIONS
  In this chick model, hyperhomocysteinemia causes greater radial and longitudinal bone growth, despite normal indices of bone formation. Although there is also evidence for an abnormal matrix and altered bone composition, our finding of normal biomechanical bone strength, once corrected for altered morphometry, suggests that any increase in the risk of long bone fracture in human hyperhomocysteinemic disease is small. We also conclude that the hCySH-supplemented chick is a promising model for study of the connective tissue abnormalities associated with homocystinuria and an important alternative model to the CBS knock-out mouse.
authors.affiliation: School of Nutrition, University of Moncton, Moncton NB E1A 3E9, Canada. massep@umoncton.ca
authors.forename: Priscilla G
authors.initials: PG
authors.lastname: Massé
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.forename: Israel
authors.initials: I
authors.lastname: Ziv
authors.forename: Peter
authors.initials: P
authors.lastname: Hauschka
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Donovan
authors.forename: David S
authors.initials: DS
authors.lastname: Howell
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
mesh_terms: D000818:Animals; D001774:Blood Chemical Analysis; D015519:Bone Density / Q000502:physiology; D001846:Bone Development / Q000502:physiology; D001847:Bone Diseases / Q000097:blood* / Q000000981:diagnostic imaging / Q000178:diet therapy*; D001857:Bone Matrix / Q000737:chemistry / Q000254:growth & development / Q000503:physiopathology; D001842:Bone and Bones / Q000737:chemistry* / Q000000981:diagnostic imaging / Q000503:physiopathology; D002645:Chickens; D004032:Diet / Q000379:methods; D004195:Disease Models, Animal; D006710:Homocysteine / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000000981:diagnostic imaging / Q000178:diet therapy / Q000378:metabolism / Q000503:physiopathology; D011859:Radiography; D013977:Tibia / Q000737:chemistry / Q000000981:diagnostic imaging / Q000254:growth & development / Q000503:physiopathology
chemical_list: D006710:Homocysteine