Linked Deficiencies in Extracellular PPi and Osteopontin Mediate Pathologic Calcification Associated With Defective PC-1 and ANK Expression

Kristen Johnson, James Goding, Deborah Van Etten, Adnan Sali, Shou Ih Hu, David Farley, Hollis E Krug, Lovisa Hessle, José Luis Millán, Robert Terkeltaub

Research output: Contribution to journalArticlepeer-review

176 Scopus citations


Osteopontin and PPi both suppress hydroxyapatite deposition. Extracellular PPi deficiency causes spontaneous hypercalcification, yet unchallenged osteopontin knockout mice have only subtle mineralization abnormalities. We report that extracellular PPi deficiency promotes osteopontin deficiency and correction of osteopontin deficiency prevents hypercalcification, suggesting synergistic inhibition of hydroxyapatite deposition. Nucleotide pyrophosphatase phosphodiesterase (NPP) isozymes including PC-1 (NPP1) function partly to generate PPi, a physiologic calcification inhibitor. PPi transport is modulated by the membrane channel protein ANK. Spontaneous articular cartilage calcification, increased vertebral cortical bone formation, and peripheral joint and intervertebral ossific ankylosis are associated with both PC-1 deficiency and expression of truncated ANK in ank/ank mice. To assess how PC-1, ANK, and PPi regulate both calcification and cell differentiation, we studied cultured PC-1-/- and ank/ank mouse calvarial osteoblasts. PC-1-/- osteoblasts demonstrated ∼50% depressed NPP activity and markedly lowered extracellular PPi associated with hypercalcification. These abnormalities were rescued by transfection of PC-1 but not of the NPP isozyme B10/NPP3. PC-1-/- and ank/ank cultured osteoblasts demonstrated not only comparable extracellular PPi depression and hypercalcification but also marked reduction in expression of osteopontin (OPN), another direct calcification inhibitor. Soluble PC-1 (which corrected extracellular PPi and OPN), and OPN itself (≥15 pg/ml), corrected hypercalcification by PC-1-/- and ank/ank osteoblasts. Thus, linked regulatory effects on extracellular PP i and OPN expression mediate the ability of PC-1 and ANK to regulate calcification.

Original languageEnglish (US)
Pages (from-to)994-1004
Number of pages11
JournalJournal of Bone and Mineral Research
Issue number6
StatePublished - Jun 1 2003


  • ANK
  • Hyperostosis
  • Progressive ankylosis
  • ttw/ttw mouse


Dive into the research topics of 'Linked Deficiencies in Extracellular PPi and Osteopontin Mediate Pathologic Calcification Associated With Defective PC-1 and ANK Expression'. Together they form a unique fingerprint.

Cite this