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Linked Deficiencies in Extracellular PP i and Osteopontin Mediate Pathologic Calcification Associated With Defective PC‐1 and ANK Expression
Author(s) -
Johnson Kristen,
Goding James,
Van Etten Deborah,
Sali Adnan,
Hu ShouIh,
Farley David,
Krug Hollis,
Hessle Lovisa,
Millán José Luis,
Terkeltaub Robert
Publication year - 2003
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.2003.18.6.994
Subject(s) - osteopontin , extracellular , ectopic calcification , calcification , chemistry , extracellular matrix , endocrinology , medicine , microbiology and biotechnology , biochemistry , biology
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 PP I , a physiologic calcification inhibitor. PP i 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 PP i 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 PP i 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 PP i depression and hypercalcification but also marked reduction in expression of osteopontin (OPN), another direct calcification inhibitor. Soluble PC‐1 (which corrected extracellular PP i 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.