Bone Abstracts (2016) 5 OC6.2 | DOI: 10.1530/boneabs.5.OC6.2

Bone with uncleavable type I collagen C-propeptide has abnormal development of multiple bone cell populations and increased bone mineral density with age

Aileen M Barnes1, Joseph E Perosky2, Stephane Blouin3, M Helen Rajpar1, Basma Khoury2, Klaus Klaushofer3, Paul Roschger3, Nadja Fratzl-Zelman3, Kenneth M Kozloff2 & Joan C Marini1


1NICHD/NIH, Bethesda, Maryland, USA; 2University of Michigan, Ann Arbor, Michigan, USA; 3Ludwig Boltzmann Institute of Osteology, Vienna, Austria.


Mutations in the C-propeptide cleavage site of both COL1A1 and COL1A2 cause dominant high bone mass (HBM) osteogenesis imperfecta (OI), characterized by bone hypermineralization. To elucidate the role of C-propeptide processing in bone formation, we generated heterozygous HBM mice in which both residues of the COL1A1 cleavage site were mutated to prevent cleavage by BMP1. HBM mice are smaller than WT in both weight and length and have extremely brittle bones.

HBM bone extracts contain pC-collagen and increased monomeric COL1A1 C-propeptide. Bone collagen fibrils have a ‘barbed-wire’ appearance, consistent with the presence of pC-collagen, while dermal fibrils were smaller and more homogeneous than WT with a loss of large fibrils.

Quantitative backscattered electron imaging (qBEI) revealed in cortical femoral bone of 2 month-old mutants an increased bone matrix mineralization: CaMean: +5% (P=0.0026), CaPeak: +6% (P=0.0002); CaHigh +470% (P=0.0018) versus WT. Femoral aBMD is decreased at 2 months but increases to 93% of WT at 1 year. Cortical and trabecular TMD by μCT are decreased versus WT at 2 months, but normalized at 1 year.

Impaired C-propeptide processing affects skeletal geometry and biomechanics. On μCT, HBM femora have thinner cortices and decreased trabecular bone volume. Mechanical testing revealed decreased femoral stiffness, yield and fracture load, with no improvement over time. HBM femora are extremely brittle; post-yield displacement is ~15% of WT (P<0.001). By 6 months, HBM mice hind limb joints are fused with severe osteoarthritis.

C-propeptide processing also influences cellular differentiation of bone. Osteoblast collagen secretion was reduced ~25% in HBM versus WT (P=0.023). Two-month HBM femurs have fewer osteocytes (P<0.001), but they are increased in area (P<0.001). TRAP staining revealed smaller osteoclasts in HBM. These changes in multiple bone cell populations support the prospective signalling function of the C-propeptide trimer, influencing collagenous, cellular and mineral properties of bone.