Classical osteogenesis imperfecta (OI) is caused by type I collagen mutations. Mutations in the C-propeptide cleavage site of both COL1A1 and COL1A2 cause high bone mass OI, characterised by bone hypermineralisation. To elucidate the role of type I procollagen C-propeptide processing in bone formation, we generated a mouse with a heterozygous C-propeptide cleavage site defect (high bone mass, HBM), substituting both COL1A1 cleavage site residues to prevent BMP1 cleavage. Western blots on long bone extracts revealed unprocessed pro- and pC-collagen and cleaved C-propeptide in HBM bone. At 2 months, male HBM mice are significantly smaller in weight (77%) and length (92%) and have shorter femurs (92%). All 2 month HBM mice have pelvic deformities; 40% have kyphosis. Femoral aBMD in HBM mice is decreased 25% (P<0.001), but vertebral BMD is normal. On μCT, HBM femora have thinner cortices with decreased cortical area. Four-point bending revealed significantly decreased HBM femoral stiffness, yield load, and ultimate load. HBM femora are also extremely brittle; post-yield displacement is only ~10% of WT (0.23 vs 0.03, P<0.001). Collagen from HBM calvarial osteoblasts had normal biochemistry with normal trimer incorporation, however, HBM osteoblasts deposited only about 50% of WT matrix. Sost transcripts in HBM femora are decreased ~40% and suggests C-propeptide processing may also influence cellular differentiation. Dermal fibril diameters were smaller and more homogeneous in HBM than WT, with loss of large fibrils. The HBM mouse phenotype is similar to that of the Bmp1−/−/Tll1−/− mouse which also has small size, thin cortices, reduced maximum load and a dramatic decrease in post-yield displacement. The HBM mouse demonstrates that the essential elements of the broader enzyme deficiency are reproduced by a substrate defect in type I C-propeptide cleavage. These data show the importance of the type I procollagen C-propeptide to both collagenous and mineral properties of bone.
Disclosure: The authors declared no competing interests.