Parathyroid hormone regulates the expression of the receptor protein tyrosine phosphatase, OST-PTP, in rat osteoblast-like cells.
Bone remodeling requires regulated tyrosine phosphorylation mediated by specific protein tyrosine kinases, such as c-src and c-fms, and to date, unknown protein tyrosine phosphatases (PTPs). We previously reported the isolation of a novel bone-specific receptor PTP, named osteotesticular PTP (OST-PTP), which is regulated during osteoblast differentiation and after exposure to PTH. To determine the relevance of this PTH regulation, we characterized the PTH-induced increase in OST-PTP messenger RNA (mRNA) in UMR 106 cells in comparison with PTH effects on a related receptor PTP and a PTH regulated gene, rat collagenase. Treatment of cells with rat PTH 1-34 (rPTH) resulted in a dramatic concentration and time-dependent increase in OST-PTP mRNA with a threshold at 4 h (= or < 1nM rPTH) and maximal response of 6- 10-fold above control levels at 8 h (100 nM rPTH). An increase in collagenase mRNA was detectable 2 h earlier at 100 pM rPTH with a maximal response at least 5-fold greater than that observed for OST- PTP. Levels of mRNA for the structurally similar PTP, rat leucocyte antigen-related molecule, were unaffected by rPTH treatment. Administration of cycloheximide (5-100 microM) abolished the OST-PTP and collagenase responses to PTH. The cAMP analogs, CPT-cAMP (0.01-1mM; 8 h) or Sp-cAMP (0.1 and 0.5 mM) were equal or greater in their effectiveness to enhance both OST-PTP and collagenase mRNA as compared with rPTH. In contrast, phorbol esters, calcium ionophore, bovine PTH (3-34), or human PTHrP (7-34) had no effect on either transcript. Interestingly, 36 h of pretreatment of cells with epidermal growth factor (10 ng/ml), a growth factor known to modulate PTH's actions, resulted in a significant decrease in the abundance of OST-PTP mRNA after rPTH exposure. These studies suggest that regulation of OST-PTP mRNA is a secondary response to PTH stimulation that is dependent on protein synthesis and that may be primarily by activation of the protein kinase A pathway. This specific modulation of a bone receptor PTP may prove to be a critical component in the PTH modulation of osteoblast function.
Mauro
L J
LJ
Department of Biological Chemistry, University of Michigan, Ann Arbor, 48109, USA.
Olmsted
E A
EA
Davis
A R
AR
Dixon
J E
JE
D000818:Animals; D010006:Osteoblasts / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis*; D051381:Rats; D011956:Receptors, Cell Surface / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D010281:Parathyroid Hormone; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D017027:Protein Tyrosine Phosphatases