Identification of a PTH regulated gene selectively induced in vivo during PTH-mediated bone formation.
The biological activities of parathyroid hormone (PTH) on bone are quite complex as demonstrated by its catabolic and anabolic activities on the skeleton. Although there have been many reports describing genes that are regulated by PTH in osteoblast cells, the goal of this study was to utilize a well-established in vivo PTH anabolic treatment regimen to identify genes that mediate bone anabolic effects of PTH. We identified a gene we named PTH anabolic induced gene in bone (PAIGB) that has been reported as brain and acute leukemia cytoplasmic (BAALC). Therefore, using the latter nomenclature, we have discovered that BAALC is a PTH-regulated gene whose mRNA expression was selectively induced in rat tibiae nearly 100-fold (maximal) by a PTH 1-34 anabolic treatment regimen in a time-dependent manner. Although BAALC is broadly expressed, PTH did not regulate BAALC expression in other PTH receptor expressing tissues and we find that the regulation of BAALC protein by PTH in vivo is confined to mature osteoblasts. Further in vitro studies using rat UMR-106 osteoblastic cells show that PTH 1-34 rapidly induces BAALC mRNA expression maximally by 4 h while the protein was induced by 8 h. In addition to being regulated by PTH 1-34, BAALC expression can also be induced by other bone forming factors including PGE(2) and 1,25 dihydroxy vitamin D(3). We determined that BAALC is regulated by PTH predominantly through the cAMP/PKA pathway. Finally, we demonstrate in MC3T3-E1 osteoblastic cells that BAALC overexpression regulates markers of osteoblast differentiation, including downregulating alkaline phosphatase and osteocalcin expression while inducing osteopontin expression. We also demonstrate that these transcriptional responses mediated by BAALC are similar to the responses elicited by PTH 1-34. These data, showing BAALC overexpression can mimic the effect of PTH on markers of osteoblast differentiation, along with the observations that BAALC is induced selectively with a bone anabolic treatment regimen of PTH (not a catabolic treatment regimen), suggest that BAALC may be an important mediator of the PTH anabolic action on bone cell function.
Robinson
John A
JA
Women's Health Research Institute, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. robinsj@wyeth.com
Susulic
Vedrana
V
Liu
Yao-Bin
YB
Taylor
Chanda
C
Hardenburg
Jill
J
Gironda
Virginia
V
Zhao
Weiguang
W
Kharode
Yogendra
Y
McLarney
Sean
S
Bai
Yuchen
Y
Malone
Daniel P
DP
Murrills
Richard
R
Bex
Fred
F
D000595:Amino Acid Sequence; D000818:Animals; D015415:Biomarkers; D002117:Calcitriol / Q000494:pharmacology; D002454:Cell Differentiation; D002478:Cells, Cultured; D017124:Conserved Sequence; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects* / Q000235:genetics*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016415:Sequence Alignment; D015398:Signal Transduction
C486704:Baalc protein, rat; D015415:Biomarkers; D009363:Neoplasm Proteins; C470125:PTH protein, human; D010281:Parathyroid Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D002117:Calcitriol; D015232:Dinoprostone