Insulin-like growth factors: actions on the skeleton

Abstract

The discovery of the growth hormone (GH)-mediated somatic factors (somatomedins), insulin-like growth factor (IGF)-I and -II, has elicited an enormous interest primarily among endocrinologists who study growth and metabolism. The advancement of molecular endocrinology over the past four decades enables investigators to re-examine and refine the established somatomedin hypothesis. Specifically, gene deletions, transgene overexpression or more recently, cell-specific gene-ablations, have enabled investigators to study the effects of the Igf1 and Igf2 genes in temporal and spatial manners. The GH/IGF axis, acting in an endocrine and autocrine/paracrine fashion, is the major axis controlling skeletal growth. Studies in rodents have clearly shown that IGFs regulate bone length of the appendicular skeleton evidenced by changes in chondrocytes of the proliferative and hypertrophic zones of the growth plate. IGFs affect radial bone growth and regulate cortical and trabecular bone properties via their effects on osteoblast, osteocyte and osteoclast function. Interactions of the IGFs with sex steroid hormones and the parathyroid hormone demonstrate the significance and complexity of the IGF axis in the skeleton. Finally, IGFs have been implicated in skeletal aging. Decreases in serum IGFs during aging have been correlated with reductions in bone mineral density and increased fracture risk. This review highlights many of the most relevant studies in the IGF research landscape, focusing in particular on IGFs effects on the skeleton.

Keywords: chondrocyte; insulin-like; osteoblast; osteoclast; osteocyte.

Figure 1. The somatotropic axis

Hypothalamic GHRH and somatostatin as well as intestine-secreted ghrelin regulate pituitary secretion of GH. Once released to circulation, GH stimulates liver production of IGFs and a few of the IGFBPs. In the vasculature IGFs are found in binary and ternary complexes, which increase their half-lives. Serum and tissue proteases act upon the IGFBPs to liberate IGFs and increase their bioavailability. Target cells expressing the IGF-IR, IR, or hybrid receptors bind the IGFs and initiate phosphorylation cascades to enhance cellular proliferation, differentiation and function. GHR is found on almost all cells. Upon binding to its receptor GH initiates signaling cascades to promote cellular function that may be IGF-dependent or independent.

Figure 2. Bone cell-specific effects of IGFs

IGFs regulate the mesenchymal and hematopoietic osteoprogenitor pools and participate in lineage commitment. In the growth plate IGFs promote clonal expansion of chondrocytes at the proliferation zone, and cellular maturation of pre-hypertrophic chondrocytes. During bone modeling and remodeling IGFs enhance osteoblastogenesis and promote matrix deposition and mineralization. Once embedded in the matrix, osteoblasts undergo terminal differentiation to osteocytes that play important roles in keeping the bone matrix integrity. Osteocytes are the bone mechano-sensors that mediate their response to loads partially via secretion of IGFs. The roles of IGFs in osteoclastogenesis are yet to be defined. IGFs can stimulate fusion of osteoclast progenitors and enhance osteoclasts resorption activity.