Abstract
Defective bone mineralization has serious clinical manifestations, including deformities and fractures, but the regulation of this extracellular process is not fully understood. We have developed a mathematical model consisting of ordinary differential equations that describe collagen maturation, production and degradation of inhibitors, and mineral nucleation and growth. We examined the roles of individual processes in generating normal and abnormal mineralization patterns characterized using two outcome measures: mineralization lag time and degree of mineralization. Model parameters describing the formation of hydroxyapatite mineral on the nucleating centers most potently affected the degree of mineralization, while the parameters describing inhibitor homeostasis most effectively changed the mineralization lag time. Of interest, a parameter describing the rate of matrix maturation emerged as being capable of counter-intuitively increasing both the mineralization lag time and the degree of mineralization. We validated the accuracy of model predictions using known diseases of bone mineralization such as osteogenesis imperfecta and X-linked hypophosphatemia. The model successfully describes the highly nonlinear mineralization dynamics, which includes an initial lag phase when osteoid is present but no mineralization is evident, then fast primary mineralization, followed by secondary mineralization characterized by a continuous slow increase in bone mineral content. The developed model can potentially predict the function for a mutated protein based on the histology of pathologic bone samples from mineralization disorders of unknown etiology.
Highlights
Defects in bone mineralization can result in reduced or excessive bone mineralization, which can lead to serious clinical manifestations, including bone deformities and fractures
The clinical phenotype of osteogenesis imperfecta can be caused by mutations in genes encoding the proteins that are involved in collagen post-translational modifications such as bone morphogenetic protein 1 (BMP1), or the proteins that regulate bone mineralization by an as yet unknown mechanism (Marini et al, 2014)
The mathematical model for bone mineralization developed in this study captures the strongly nonlinear dynamics of mineralization, which starts from a lag phase when osteoid is present but no mineralization is evident, followed by fast primary mineralization, and subsequent secondary mineralization characterized by a continuous slow increase in bone mineral content (Roschger et al, 2008b)
Summary
Defects in bone mineralization can result in reduced or excessive bone mineralization, which can lead to serious clinical manifestations, including bone deformities and fractures. Numerous conditions which are not associated with abnormal levels of circulating calcium and phosphate are known to result in hypo- or hypermineralization of bone matrix (Roughley et al, 2003). One example is osteogenesis imperfecta, a disease usually caused by mutations in collagen type I-encoding genes and characterized by increased bone mineralization (Roschger et al, 2008a; Forlino et al, 2011). The clinical phenotype of osteogenesis imperfecta can be caused by mutations in genes encoding the proteins that are involved in collagen post-translational modifications such as bone morphogenetic protein 1 (BMP1), or the proteins that regulate bone mineralization by an as yet unknown mechanism (Marini et al, 2014). The mechanisms underlying the development of hypo- and hypermineralization of extracellular bone matrix when the plasma levels of calcium and phosphate are within the normal range are complex and not well understood
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