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カルシウムとリン酸イオン(Pi)からなるヒドロキシアパタイト結晶が,コラーゲン線維に付着し成長して骨は石灰化する。石灰化は,ピロリン酸(PPi)やSIBLINGタンパク質群などにより阻害され,これらの活性は,PPi産生酵素ENPP1,PPi輸送タンパク質ANK,PPi分解酵素/Pi産生酵素ALPL,リン酸調節中性エンドペプチダーゼPHEXなどによって調節される。骨でのヒドロキシアパタイト結晶核の形成に,骨芽細胞が分泌する基質小胞が必須かどうかには異論があるが,基質小胞の膜が破れた後の結晶は,石灰化球として成長する。石灰化阻害機構の破綻は,異所性石灰化などのミネラリゼーション異常を起こす。
Bone is mineralized when hydroxyapatite crystals derived from calcium ions and inorganic phosphate(Pi)grow along collagen fibrils in the extracellular matrix. Mineralization is initiated by nucleation of those crystals. Mature osteoblasts secrete matrix vesicles into osteoid, which contain growing hydroxyapatite crystal seeds. After rupture of the lipid bilayer of those vesicles, crystals continue to grow as a mineralized nodule and adhere to collagen fibrils. It remains controversial whether nucleation occurs mainly in matrix vesicles or also extra-vesicularly around collagen fibrils. Mineralization is inhibited by pyrophosphate(PPi)and by SIBLING family proteins, which carry an acidic serine- and aspartate-rich motif(ASARM)and include osteopontin, dentin matrix protein 1 and MEPE. Intracellular and extracellular activity of these factors is regulated by the PPi-generating ectonucleotide pyrophosphatase/phosphodiesterase(ENPP1),the PPi-transporter progressive ankylosis(ANK)protein, the PPi-degrading/Pi-generating ectoenzyme alkaline phosphatase(ALPL, TNAP),and PHEX endopeptidase. Gain- or loss-of-function mutations in genes encoding these proteins are associated with mineralization disorders such as ectopic calcification and other pathologies.