Insulin Like Growth Factor-I: A Critical Mediator of the Skeletal Response to Parathyroid Hormone

Abstract

This review focuses on the mechanisms by which PTH stimulates both osteoblast and osteoclast function, emphasizing the critical role that IGF-I plays in these processes. After reviewing the current literature on the skeletal actions of PTH and the modulation of IGF action on bone by the different IGF-binding proteins, the review then examines studies from mouse models in which IGF-I or its receptor have been selectively deleted in different cells of the skeletal system, in particular osteoprogenitors, mature osteoblasts, and osteoclasts. Mice in which IGF-I production has been deleted from all cells are deficient in both bone formation and bone resorption with few osteoblasts or osteoclasts in bone in vivo, reduced osteoblast colony forming units, and an inability of either the osteoblasts or osteoclast precursors to support osteoclastogenesis in vitro.Mice in which the IGF-I receptor is specifically deleted in mature osteoblasts have a mineralization defect in vivo, and bone marrow stromal cells from these mice fail to mineralize in vitro. Mice in which the IGF-I receptor is deleted in osteoprogenitor cells have a marked reduction in osteoblast proliferation and differentiation leading to osteopenia. Finally mice lacking the IGF-I receptor in their osteoclasts have increased bone and decreased osteoclast formation. PTH fails to stimulate bone formation in the mice lacking IGF-I or its receptor in osteoblasts or enhance the signaling between osteoblasts and osteoclasts through RANKL/RANK and Ephrin B2/Eph B4, emphasizing the role IGF-I signaling plays in cell-communication per se and as stimulated by PTH.

Ameloblastin, an Extracellular Matrix Protein, Affects Long Bone Growth and Mineralization

“…A PCR array employed during our quest for an explanation of the unexpected growth reduction in AMBN mice identified IGF1 as the second most deregulated gene product and possible candidate for changes in osteoblast proliferation and overall growth rate. IGF1 is the most abundant growth factor produced by osteoblasts (36,37) and is thought to be responsible for the maintenance of a physiological pace of proliferation in the skeletal system. (38)(39)(40) Low levels of IGF1 have been associated with dwarfism and Laron syndrome, and Igf1 null mice exhibit impaired postnatal growth and defects in longitudinal bone growth.…”

Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development

“…Neutralizing antibodies for IGF-I block the stimulatory effects of PTH on collagen synthesis (80) and osteoblast differentiation (81). Intermittent PTH fails to elicit skeletal anabolism in global IGF-I KO mice (51,(82)(83), or in mice lacking the expression of IRS-1 (84). Similarly, ablation of IGF-IR in mature osteoblasts prevents the anabolic effects of intermittent PTH in OCN IGF-IR -/-mice (59).…”

Bone Formation Deregulations Are the Oncogenesis Keys in Osteosarcomas

“…In normal bone formation, IGF-I and II are known to have effects on cell proliferation and to be inducer of collagen synthesis (Bikle &Wang, 2011;Wang et al, 2006). The recent findings demonstrated that the lack of IGF-I or its receptor in osteoblasts is enhancing the signaling between osteoblasts and osteoclasts through RANKL/RANK or PTH.…”