In vivo comparison of activated protein-1 gene activation in response to human parathyroid hormone (hPTH)(1-34) and hPTH(1-84) in the distal femur metaphyses of young mice

Bone. 2000 Dec;27(6):819-26. doi: 10.1016/s8756-3282(00)00391-4.

Abstract

Intermittent parathyroid hormone (PTH) treatment increases bone mass in humans and animals. Although intact human PTH has 84 amino acids, the N-terminal 31 to 38 amino acids are sufficient for bone anabolic activity in vivo. Prior studies have evaluated hPTH(1-34) and hPTH(1-84) with respect to bone mass increase and quality, but there have been no in vivo comparisons of dose-dependent molecular responses. After confirming that young male BALB/c mice respond to daily PTH with increased bone mass, we profiled the steady-state mRNA levels of activating protein-1 (AP-1) genes regulated by hPTH(1-34) and hPTH(1-84) at doses ranging from 0 to 19.4 nmol/kg in the distal femur metaphyses. We selected AP-1 genes, which include jun and fos, as they play a fundamental role mediating signals for proliferation, differentiation, and apoptosis in cells of different origins, including bone, and are known to be regulated by PTH. Human PTH(1-34) and hPTH(1-84) increased steady-state mRNA expression of c-jun, junB, c-fos, and fra-2 in an equivalent dose- and time-dependent manner. Expression of fosB or fra-1 was not detected with either peptide. When averaged across dose and time, responses to hPTH(1-34) and hPTH(1-84) were not significantly different from each other. Expression of c-jun, junB, and c-fos peaked 30 minutes after the injection while fra-2 expression peaked 30 minutes later. All AP-1 genes stimulated by PTH returned to the levels of vehicle treated controls by 3 h after injection. The expression level of junD, which was abundant in the distal metaphysis, was not altered by either peptide. No change in magnitude was observed after 1, 3, or 7 days of once-daily subcutaneous treatment of either peptide. When individual comparisons for each dose between peptides were made, the minimum effective dose necessary to stimulate a significant increase in c-fos and junB expression was equivalent for both peptides. The minimum effective dose for hPTH(1-34) was at least tenfold lower than hPTH(1-84) in stimulating c-jun and fra-2 expression. Area under the curve for the highest dose (19.4 nmol/kg) of either peptide showed no significant differences in the expression of any of the genes. In conclusion, in young mice given once-daily subcutaneous injections up to 7 days, hPTH(1-34) and hPTH(1-84) induced equivalent responses by time and dose in the selected AP-1 genes. These data on molecular regulation in mouse bone confirm and extend prior data from rat studies showing equivalence on bone mass at equimolar doses.

Publication types

  • Comparative Study

MeSH terms

  • Age Factors
  • Animals
  • Dose-Response Relationship, Drug
  • Femur / cytology
  • Femur / drug effects*
  • Femur / metabolism
  • Gene Expression / drug effects
  • Genes, fos / physiology
  • Genes, jun / physiology
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Organ Size
  • Osteoblasts / drug effects
  • Osteoblasts / physiology
  • Parathyroid Hormone / pharmacology*
  • Peptide Fragments / pharmacology*
  • Proto-Oncogene Proteins c-fos / genetics
  • RNA, Messenger / analysis
  • Time Factors
  • Transcription Factor AP-1 / genetics*

Substances

  • Parathyroid Hormone
  • Peptide Fragments
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Transcription Factor AP-1
  • fos-related antigen 1