Dependence of increased linear bone growth on age at oMT1a-oGH transgene expression in mice.

We have previously shown that growth hormone (GH) accelerates the rate and extends the duration of linear bone growth in a GH-transgenic mouse model. To determine if this GH effect was temporally regulated, bone lengths and growth plate widths were determined in transgenic mice carrying an ovine metallothionein 1a-ovine growth hormone (oMT1a-oGH) transgene. Transgene expression was initiated in oMT1a-oGH hemizygous transgenic mice by addition of 25 mM ZnSO4 to the water at 21 d of age; littermate control mice were also ZnSO4 supplemented. These mice were maintained on ZnSO4 until 70 d of age at which time the mice were killed and the ulna, humerus, and tibia were collected. Additional transgenic and control mice were stimulated at 21 d and the ZnSO4 stimulus withdrawn after 21 d of treatment and killed at 70 d or stimulated at 28 d with the stimulus withdrawn after 28 d and killed at 70 d. Continuously stimulated transgenic mice had longer bones than those of comparable control mice. The increased bone length in the transgenics was correlated with wider growth plates. Transgene expression initiated at 21 d of age increased bone length to the same or greater extent than that observed for mice with transgene expression initiated at 28 d but maintained for a longer interval thereby indicating that the age of GH initiation is more critical in bone elongation than the duration of GH exposure. The elevated GH effects were independent of circulating thyroid hormones and attainment of puberty. Elevated GH also increased the widths of all growth plate zones to the same extent by increasing cell numbers, rather than enhancing matrix production or individual cellular area.