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Bone Abstracts (2017) 6 OC22 | DOI: 10.1530/boneabs.6.OC22

ICCBH2017 Oral Communications (1) (26 abstracts)

Type I collagen C-propeptide cleavage deficiency increases bone mineralization and alters bone cell differentiation

Aileen Barnes 1 , Joseph Perosky 2 , Stéphane Blouin 3 , M. Helen Rajpar 1 , Basma Khoury 2 , MaryAnn Weis 4 , Klaus Klaushofer 3 , Paul Roschger 3 , David Eyre 4 , Nadja Fratzl-Zelman 3 , Kenneth Kozloff 2 & Joan Marini 1

1NICHD/NIH, Bethesda, MD, USA; 2University of Michigan, Ann Arbor, MI, USA; 3Ludwig Boltzmann Institute of Osteology, Vienna, Austria; 4University of Washington, Seattle, WA, USA.

High Bone Mass (HBM) osteogenesis imperfecta (OI) is caused by dominant mutations in the C-propeptide cleavage site of COL1A1 or COL1A2, characterized by bone hypermineralization. To elucidate the role of C-propeptide processing in bone mineralization and development, we generated heterozygous HBM mice with both residues (Ala-Asp) of the COL1A1 cleavage site substituted (Thr-Asn) to prevent processing by BMP1. Two, 6- and 12-month WT and HBM bones were examined for histology, mineralization, mechanics, and cell differentiation. HBM mice are smaller than WT in weight and length throughout life. Their femoral extracts contain pC-collagen and increased monomeric COL1A1 C-propeptide, resulting in a ‘barbed-wire’ appearance to bone collagen fibrils, thin cortices and decreased BV/TV. By 6 months, HBM mice hind limb joints fuse with severe osteoarthritis. HBM femora have decreased stiffness, yield and fracture load, which did not improve with age. Their femora are also extremely brittle; post-yield displacement is ~15% of WT (P<0.001). HBM femora have decreased collagen content (59% of WT) with an increase in mature (HP) and total (HP+LP) crosslinks. Femoral aBMD is decreased at 2-months but is near normal (93%) at 1 year. On μ-CT, HBM cortical and trabecular TMD are normalized at 1 year. Using quantitative backscattered electron imaging (qBEI) to assay mineral content, HBM cortical bone had increased CaMean, CaPeak and CaHigh at 2- and 6- and 12-months compared to WT. HBM CaPeak increased significantly between 6- and 12-months, although WT levels peaked at 6 months. There is a complementary decrease in HBM percent body fat at 6- and 12-months. Bone cell differentiation was also affected in HBM. Femoral Bglap transcripts are decreased, as was osteoblast collagen secretion. HBM femora had fewer osteocyte lacunae (P<0.01) but increased lacunar area at 2-, 6- and 12-months (P<0.001). HBM serum TRAP and PINP were significantly increased, consistent with increased femoral transcripts of Ctsk, Acp5 and the Rankl/Opg ratio. Murine HBM bone mineralization is increased throughout life and increases with age, even after WT mineralization has peaked, raising concerns for long-term patient status. Alterations in multiple bone cell populations support a putative C-propeptide trimer signalling function, influencing bone matrix and mineralization.

Disclosure: The authors declared no competing interests.

Volume 6

8th International Conference on Children's Bone Health


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