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. 2000

D Stanislaus, and V Devanarayan, and J M Hock
Lilly Research Laboratories, Indianapolis, IN 46202, USA.

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.

UI MeSH Term Description Entries
D008297 Male Males
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D009929 Organ Size The measurement of an organ in volume, mass, or heaviness. Organ Volume,Organ Weight,Size, Organ,Weight, Organ
D010006 Osteoblasts Bone-forming cells which secrete an EXTRACELLULAR MATRIX. HYDROXYAPATITE crystals are then deposited into the matrix to form bone. Osteoblast
D010281 Parathyroid Hormone A polypeptide hormone (84 amino acid residues) secreted by the PARATHYROID GLANDS which performs the essential role of maintaining intracellular CALCIUM levels in the body. Parathyroid hormone increases intracellular calcium by promoting the release of CALCIUM from BONE, increases the intestinal absorption of calcium, increases the renal tubular reabsorption of calcium, and increases the renal excretion of phosphates. Natpara,PTH (1-84),PTH(1-34),Parathormone,Parathyrin,Parathyroid Hormone (1-34),Parathyroid Hormone (1-84),Parathyroid Hormone Peptide (1-34),Hormone, Parathyroid
D010446 Peptide Fragments Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques. Peptide Fragment,Fragment, Peptide,Fragments, Peptide
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005269 Femur The longest and largest bone of the skeleton, it is situated between the hip and the knee. Trochanter,Greater Trochanter,Lesser Trochanter,Femurs,Greater Trochanters,Lesser Trochanters,Trochanter, Greater,Trochanter, Lesser,Trochanters,Trochanters, Greater,Trochanters, Lesser
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000367 Age Factors Age as a constituent element or influence contributing to the production of a result. It may be applicable to the cause or the effect of a circumstance. It is used with human or animal concepts but should be differentiated from AGING, a physiological process, and TIME FACTORS which refers only to the passage of time. Age Reporting,Age Factor,Factor, Age,Factors, Age

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