Bone turnover and type I collagen C-telopeptide isomerization in adult osteogenesis imperfecta: associations with collagen gene mutations.
BACKGROUND
Increased bone fragility in osteogenesis imperfecta (OI) is not totally accounted for by decreased bone mineral density (BMD), and alterations of type I collagen (Col I) are believed to play a role. Newly synthesized Col I comprises non isomerized C-telopeptide (alphaCTX), but with bone matrix maturation alphaCTX is converted to its isomerized beta form (betaCTX). Urinary alpha/betaCTX ratio has been proposed to reflect collagen maturation. We investigated changes in bone turnover and Col I isomerization in adult patients with OI and their relationship with Col I gene mutations.


METHODS
Sixty four adult patients [25 women, 39 men mean age (SD): 36.2 (11.6) years] with OI participating in a randomized study and 64 healthy controls of similar age and gender distribution were investigated. In patients with OI and controls, we measured the following biochemical markers of bone metabolism: serum type I collagen N-propeptide (PINP) an index of Col I synthesis, osteocalcin a marker of osteoblastic activity, urinary Col I helical peptide, a marker reflecting the degradation of the helical portion of Col I, urinary alphaCTX and urinary and serum betaCTX. Based on the putative functional effects of Col I gene mutations which were identified in 56 OI subjects, patients were divided in those with haploinsufficiency (n=29), patients presenting with helical domain alterations (n=17) and others (n=10).


RESULTS
Compared to healthy controls, patients with OI had decreased levels of PINP (-22.7%, p<0.0001), increased osteocalcin (+73%, p<0.0001) and increased Col I helical peptide (+58%, p=0.0007). Urinary alphaCTX was increased (+31%, p=0.03) whereas urinary (-15%, p=0.022) and serum (-9.9%, p=0.0056) betaCTX were significantly decreased, resulting in a 49% (p<0.001) higher urinary alpha/betaCTX ratio. Patients with Col I gene mutations resulting in haploinsufficiency had lower PINP levels than patients with helical domain alterations (26.4+/-15.3 vs 41.6+/-27.4 ng/ml, p=0.0043) and controls (p<0.01).


CONCLUSIONS
Adults with OI are characterized by decreased Col I synthesis - especially those with haploinsufficiency mutations - increased Col I degradation and decreased Col I C-telopeptide isomerization.
Garnero
Patrick
P
INSERM Research Unit 664, Lyon, France. patrick.garnero@synarc.com
Schott
Anne-Marie
AM
Prockop
Darwin
D
Chevrel
Guillaume
G
D000328:Adult; D000595:Amino Acid Sequence; D015415:Biomarkers / Q000378:metabolism; D001842:Bone and Bones / Q000737:chemistry / Q000378:metabolism; D003094:Collagen / Q000235:genetics*; D024042:Collagen Type I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D003430:Cross-Sectional Studies; D005260:Female; D050723:Fractures, Bone; D006801:Humans; D007536:Isomerism; D008297:Male; D015394:Molecular Structure; D009154:Mutation; D010013:Osteogenesis Imperfecta / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D016032:Randomized Controlled Trials as Topic
D015415:Biomarkers; D024042:Collagen Type I; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen