Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth

Abstract

The possibility that growth hormone (GH) has effects on long bone growth independent of insulin-like growth factor-I (IGF-I) has long been debated. If this is true, then long bone growth should be more profoundly affected by the absence of GH (since both GH and GH-stimulated IGF-I effects are absent) than by the absence of IGF-I alone (since GH is still present and actually elevated). To test this hypothesis, we compared long bone growth in mice with targeted deletions of Igf1 vs growth hormone receptor (Ghr). Tibial linear growth rate was reduced by approximately 35% in Igf1 null mice and by about 65% in Ghr null mice between postnatal days 20 and 40, a time of peak GH effect during normal longitudinal growth. The Igf1 null mouse growth plate demonstrated significant enlargement of the germinal zone; chondrocyte proliferation and numbers were normal but chondrocyte hypertrophy was significantly reduced. In contrast, the Ghr null mouse germinal zone was hypoplastic, chondrocyte proliferation and numbers were significantly reduced, and chondrocyte hypertrophy was also reduced. We have previously demonstrated that IGF-II is highly expressed in growth plate germinal and proliferative zones, so we considered the possibility that GH-stimulated IGF-II production might promote germinal zone expansion and maintain normal proliferation in the Igf1 null mouse growth plate. Supporting this view, IGF-II mRNA was increased in the Igf1 null mouse and decreased in the Ghr null mouse growth plate.Thus, in the complete absence of IGF-I but in the presence of elevated GH in the Igf1 null mouse, reduction in chondrocyte hypertrophy appears to be the major defect in longitudinal bone growth. In the complete absence of a GH effect in the Ghr null mouse, however, both chondrocyte generation and hypertrophy are compromised, leading to a compound deficit in long bone growth. These observations support dual roles for GH in promoting longitudinal bone growth: an IGF-I-independent role in growth plate chondrocyte generation and an IGF-Idependent role in promoting chondrocyte hypertrophy. The question of whether GH has direct effects on chondrocyte generation is still not settled, however, since it now appears that IGF-II may medicate some of these effects on the growth plate.

A botulinum toxin–derived targeted secretion inhibitor downregulates the GH/IGF1 axis

“…Concomitant inhibition of both GH and IGF1 secretion in our model did not allow determination of their respective contributions to organ growth, as offered by genetically modified mice or hypophysectomized/supplemented rats, which indicate that liver size is mainly determined by GH action (56,57), whereas kidney size is more sensitive to IGF1 (58). Our results also confirm that bone development, and especially clonal expansion in individual growth plate chondrocyte columns, is highly sensitive to GH and IGF1 levels, as previously reported (16,19,23,24). Low doses of SXN101742 produced a smaller reduction in circulating IGF1 levels than higher doses, but achieved almost the same level of bone mass deficiency, supporting the importance of direct GH action on bone development and longitudinal growth (59).…”

SOCS2 is the critical regulator of GH action in murine growth plate chondrogenesis

“…(70) The divergence in body length and weight in SOCS2 À/À mice was noted to occur at about 3 weeks of age, and this is consistent with the knowledge that GH is the major regulator of postnatal growth in mice, where peak GH activity occurs between postnatal days 20 and 40. (71) The reasons for the sexual dimorphic differences in growth of SOCS2 À/À mice noted here and elsewhere are unclear but are likely to involve estrogen's modulatory actions on GH signaling through the stimulation of SOCS2 expression. (28,72,73) This divergence in body length between WT and SOCS2 À/À mice at approximately 3 weeks of age was associated with increased rate of bone growth in which BGR was similar in 3-week-old WT and SOCS2 À/À mice but was significantly greater in the SOCS2 À/À mice at 6 weeks of age.…”

Inactivation of Pten in Osteo-Chondroprogenitor Cells Leads to Epiphyseal Growth Plate Abnormalities and Skeletal Overgrowth

“…(48)(49)(50)(51)(52) Also of potential relevance is the synergism between Runx2 (expressed in hypertrophic chondrocytes and osteoblasts) and PI3K→Akt that is regulated by Pten. (53) The increased responsiveness of cells might be reflected in increased cell proliferation, decreased apoptosis, increased cell size, and protein translation, as well as altered differentiation.…”