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.
- SourceAvailable from: InTechOsteosarcoma, 04/2012; , ISBN: 978-953-51-0506-0
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ABSTRACT: Limited information is available on the role of MAPK phosphatase1 (MKP1) signaling in osteoblasts. We have recently reported distinct roles for MKP1 during osteoblast proliferation, differentiation and skeletal responsiveness to parathyroid hormone (PTH). Since MKP1 regulates the phosphorylation status of MAPKs we investigated the involvement of P-ERK and P-p38 MAPKs in MKP1 knock out (KO) early and mature osteoblasts with respect to mineralization and PTH response. Calvarial osteoblasts from 9-14 week old wild type (WT) and MKP1 KO male and female mice were examined. Western blot analysis revealed down-regulation and sustained expressions of P-ERK and P-p38 with PTH treatment in differentiated osteoblasts derived from KO males and females respectively. Exposure of early osteoblasts to p38 inhibitor, SB203580 (S), markedly inhibited mineralization in WT and KO osteoblasts from both genders as determined by von Kossa assay. In osteoblasts from males, ERK inhibitor U0126 (U), not p38 inhibitor (S), prevented the inhibitory effects of PTH on mineralization in early or mature osteoblasts. In osteoblasts from KO females, PTH sustained mineralization in early osteoblasts and decreased mineralization in mature cells. This effect of PTH was attenuated by S in early osteoblasts, and by U in mature KO cells. Changes in matrix gla protein (MGP) expression with PTH in KO osteoblasts did not correlate with mineralization, indicative of MKP1 dependent additional mechanisms essential for PTH action on osteoblast mineralization. We conclude that PTH regulation of osteoblast mineralization in female mice is maturation stage specific and involves MKP1 modulation of P-ERK and P-p38 MAPKs.Journal of Endocrinology 11/2012; DOI:10.1530/JOE-12-0372 · 3.59 Impact Factor
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ABSTRACT: Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor- γ (PPAR γ ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPAR γ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β -catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.12/2013; 2013:684736. DOI:10.1155/2013/684736