HiPER1, a phosphatase of the endoplasmic reticulum with a role in chondrocyte maturation

Paul R. Romano, Jun Wang, Regis J. O'Keefe, J. Edward Puzas, Randy N. Rosier, Paul R. Reynolds

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


We have previously identified and partially cloned band 17, a gene expressed in growth plate chondrocytes transiting from proliferation to hypertrophy. We now rename this gene HiPER1, Histidine Phosphatase of the Endoplasmic Reticulum-1, based on the results reported here, HiPER1 encodes two proteins of 318 (HiPER1318) and 449 (HiPER1449) amino acids, which are 20-21% identical to a group of yeast acid phosphatases that are in the histidine phosphatase family. HiPER1449 is significantly more abundant than HiPER1318, correlating with the abundance of the alternatively spliced messages encoding HiPER449 and HiPER318, Anti-HiPER1 antibodies detect two proteins of 53 and 55 kDa in growth plate chondrocytes that are absent in articular chondrocytes. We confirm that the 53 and 55 kDa proteins are HiPER1449 by heterologous expression of the HiPER1449 coding sequence in chick embryo fibroblasts. The 53 and 55 kDa proteins are glycosylated forms of HiPER1449, as N-glycosidase F digestion reduces these proteins to 48 kDa, the predicted size of HiPER1449 without the N-terminal signal sequence. Immunocytochemistry demonstrates that HiPER1449 is found in chondrocytes maturing from proliferation to hypertrophy, but is not detectable in resting zone, deep hypertrophic zone or articular chondrocytes, a distribution that is consistent with the message distribution, HiPER1449 was predicted to localize to the lumen of endoplasmic reticulum by an N-terminal signal sequence and by the C-terminal sequence Ala-Asp-Glu-Leu, which closely matches the consensus signal for ER retention, Lys-Asp-Glu-Leu. We confirm this prediction by demonstrating colocalization of HiPER1449 with the ER protein HSP47 using dual-label immunofluorescence. PTHrP, a peptide that prevents hypertrophy in chondrocytes, suppressed HiPER1 and HiPER1449 expression in vitro, an observation that further supports a role for HiPER1 in chondrocyte maturation. The yeast phosphatase homology, localization to the endoplasmic reticulum and pattern of expression suggest that HiPER1 represents a previously unrecognized intracellular pathway, involved in differentiation of chondrocytes.

Original languageEnglish
Pages (from-to)803-813
Number of pages11
JournalJournal of cell science
Issue number6
StatePublished - 1998


  • Chondrocyte differentiation
  • Endoplasmic reticulum
  • Phosphatase


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