Phosphorylation of Extracellular Bone Matrix Proteins and Its Contribution to Bone Fragility

Phosphorylation of bone matrix proteins is of fundamental importance to all vertebrates including humans. However, it is currently unknown whether increase or decline of total protein phosphorylation levels, particularly in hypophosphatemia-related osteoporosis, osteomalacia, and rickets, contribute to bone fracture. To address this gap, we combined biochemical measurements with mechanical evaluation of bone to discern fracture characteristics associated with age-related development of skeletal fragility in relation to total phosphorylation levels of bone matrix proteins and one of the key representatives of bone matrix phosphoproteins, osteopontin (OPN). Here for the first time, we report that as people age the total phosphorylation level declines by approximately 20% for bone matrix proteins and approximately 30% for OPN in the ninth decade of human life. Moreover, our results suggest that the decline of total protein phosphorylation of extracellular matrix (ECM) contributes to bone fragility, but less pronouncedly than glycation. We theorize that the separation of two sources of OPN negative charges, acidic backbone amino acids and phosphorylation, would be nature's means of assuring that OPN functions in both energy dissipation and biomineralization. We propose that total phosphorylation decline could be an important contributor to the development of osteoporosis, increased fracture risk and skeletal fragility. Targeting the enzymes kinase FamC20 and bone alkaline phosphatase involved in the regulation of matrix proteins' phosphorylation could be a means for the development of suitable therapeutic treatments. © 2018 American Society for Bone and Mineral Research.