Atypical localization of Paget's Disease of bone: a case series and systematic review of the literature

Bandeira, Franciso; Vasconcellos, Larissa Ingrid Frazao; Souza, Lílian Azevedo de

doi:10.5455/ijmrcr.paget-disease-bone

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“…For instance, engineering osteocalcin for bone remodeling could be utilized in treatments for osteoporosis. 12 Conditions under which osteocalcin delays bone growth could be modified to support treatments for Paget's disease, 13 and knowledge of the molecular mechanisms for mineralization can inform drug design.…”

Section: ■ Introductionmentioning

confidence: 99%

Osteocalcin: Promoter or Inhibitor of Hydroxyapatite Growth?

Tavakol,

Liu,

Hoff

et al. 2024

Langmuir

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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 γcarboxylglutamic 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.

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Section: ■ Introductionmentioning

confidence: 99%