Teasing Apart GH from IGF-I Effects on Longitudinal Bone Growth

Wang and colleagues examined tibial growth in mice with targeted deletions of the insulin-like growth factor-I gene (Igf1) or growth hormone (GH) receptor gene (Ghr) to elucidate the direct versus indirect (ie IGF-I-mediated) effects of GH on longitudinal bone growth. The study design was based on the fact that Igf1^-/- mice do not produce IGF-I in either the circulation or local tissues, but have high levels of GH due to the loss of IGF-I negative feedback. They would therefore be expected to retain any IGF-I-independent effects of GH action. In contrast, Ghr ^-/- mice lose all GH effects. The authors focused on tibial growth from postnatal days 20 to 40, a period of maximal GH action in normal murine growth which precedes sexual maturity. Further, because the two genetic mutants were created in different background mouse strains, all results were analyzed as a percent of the wild-type littermates. This controls for both genetic variations between the two strains and for any uterine or environmental factors that may affect growth.

Body weights of both mutants were about 60% less than wild-type littermates. Tibial morphology remained grossly normal in both, but the tibial growth rate was about 37% less in Igf1^-/- mice and 65% less in Ghr^-/- mice. The germinal zone, the upper growth plate region that produces chondrocyte precursors, was enlarged in Igf1^-/- mice but smaller in Ghr^-/- mice, suggesting IGF-I-independent effect of GH. IGF-II mRNA levels, as assessed by in situ hybridization, were increased in the former and decreased in the latter mutants. Similarly, the proliferative zone was unaffected in Igf1^-/- mice but diminished in Ghr^-/- mice; here, too, IGF-II mRNA was increased in the former but decreased in the latter. In contrast, the hypertrophic zone was markedly reduced in both mutants. It remains unresolved whether prechondrocyte proliferation is directly enhanced by GH or by GH-induced local IGF-II production.

Wang J, Zhou J, Cheng CM, Kopchick JJ, Bondy CA. Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth. J Endocrinol 2004;180:247-255.

Editor’s Comment: Confirming similar results in femoral studies of different genetic mouse strains, this paper nicely demonstrated IGF-I-independent effects of GH on chondrocyte production and proliferation, and IGF-I-dependent effects on chondrocyte hypertrophy in murine tibial growth plates. It also opens the possibility that the IGF-I-independent effects may be mediated by GH-induced local production of IGF-II. Similar analyses in Igf-II^-/- mice will be needed to answer this question, as are additional experimental models to determine the contribution of IGF-II in a physiologic context as opposed to a possibly compensatory role when IGF-I is deleted. A study comparing Igf1^-/-, Igf-II^-/- and GH deficient lit/lit mice found a greater contribution of IGF-I than IGF-II to bone mineral accretion and pubertal bone growth.¹ Thus, more than 10 years after the first description of the Igf1^-/- and Igf-II^-/- mice continue to teach us.² For an excellent review of the GH/IGF system in controlling somatic growth, see reference 3.

Adda Grimberg, MD

References - (linked to )

1. Mohan S, Richman C, Guo R, Amaar Y, Donahue LR, Wergedal J, Baylink DJ. Insulin-like growth factor regulates peak bone mineral density in mice by both growth hormone-dependent and -independent mechanisms.Endocrinology 2003;144:929-936.
2. Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993;75:73-82.
3. Butler AA, Le Roith D.Control of growth by the somatropic axis: growth hormone and the insulin-like growth factors have related and independent roles. Annu Rev Physiol 2001;63:141-164.