Hyperosteoidosis and Hypermineralization in the Same Bone: Bone Tissue Analyses in a Boy with a Homozygous BMP1 Mutation

Recently, homozygous mutations in BMP1 were identified as a cause of bone fragility in children with high areal bone mineral density. We examined iliac bone tissue from a 12-year-old boy with a homozygous mutation that leads to a p.Gly12Arg change in the signal peptide of BMP1, an enzyme that cleaves C-propeptide off the procollagen type I molecule. Histomorphometric analyses revealed marked hyperosteoidosis, with osteoid volume per bone volume at approximately 11 SD above the mean value for controls. At the same time, quantitative backscattered electron imaging showed drastic hypermineralization of mineralized bone matrix. Ca-Peak, representing the most frequently observed calcium content of mineralized matrix in trabecular bone, was 9 SD above the mean for the control population, corresponding to a 21 % higher calcium content in the patient specimen than in the average control sample. These results are similar to those that were previously reported in an individual who had a mutation in the C-propeptide cleavage site of procollagen type I. It thus appears that disturbed C-propeptide cleavage impairs mineralization in two ways: first, the onset of mineralization is delayed, leading to an increased amount of unmineralized osteoid, and second, once mineralization starts, too much mineral is incorporated into the bone matrix, resulting in hypermineralization.