Osteocalcin: Promoter or Inhibitor of Hydroxyapatite Growth?

Osteocalcin
is the most abundant noncollagenous bone protein and
the functions in bone remineralization as well as in inhibition of
bone growth have remained unclear. In this contribution, we explain
the dual role of osteocalcin in the nucleation of new calcium phosphate
during bone remodeling and in the inhibition of hydroxyapatite crystal
growth at the molecular scale. The mechanism was derived using pH-resolved
all-atom models for the protein, phosphate species, and hydroxyapatite,
along with molecular dynamics simulations and experimental and clinical
observations. Osteocalcin binds to (hkl) hydroxyapatite
surfaces through multiple residues, identified in this work, and the
fingerprint of binding residues varies as a function of the (hkl) crystal facet and pH value. On balance, the affinity
of osteocalcin to hydroxyapatite slows down crystal growth. The unique
tricalcium γ-carboxylglutamic acid (Gla) domain hereby rarely
adsorbs to hydroxyapatite surfaces and faces instead toward the solution.
The Gla domain enables prenucleation of calcium phosphate for new
bone formation at a slightly acidic pH of 5. The growth of prenucleation
clusters of calcium phosphate continues upon increase in pH value
from 5 to 7 and is much less favorable, or not observed, on the native
osteocalcin structure at and above neutral pH values of 7. The results
provide mechanistic insight into the early stages of bone remodeling
from the molecular scale, help inform mutations of osteocalcin to
modify binding to apatites, support drug design, and guide toward
potential cures for osteoporosis and hyperosteogeny.