Insulin- like Growth Factor-Binding Protein Action in Bone Tissue: A Key Role for Pregnancy- Associated Plasma Protein-A

Abstract

The insulin-like growth factor (IGF) axis is required for the differentiation, development, and maintenance of bone tissue. Accordingly, dysregulation of this axis is associated with various skeletal pathologies including growth abnormalities and compromised bone structure. It is becoming increasingly apparent that the action of the IGF axis must be viewed holistically taking into account not just the actions of the growth factors and receptors, but also the influence of soluble high affinity IGF binding proteins (IGFBPs).There is a recognition that IGFBPs exert IGF-dependent and IGF-independent effects in bone and other tissues and that an understanding of the mechanisms of action of IGFBPs and their regulation in the pericellular environment impact critically on tissue physiology. In this respect, a group of IGFBP proteinases (which may be considered as ancillary members of the IGF axis) play a crucial role in regulating IGFBP function. In this model, cleavage of IGFBPs by specific proteinases into fragments with lower affinity for growth factor(s) regulates the partition of IGFs between IGFBPs and cell surface IGF receptors. In this review, we examine the importance of IGFBP function in bone tissue with special emphasis on the role of pregnancy associated plasma protein-A (PAPP-A). We examine the function of PAPP-A primarily as an IGFBP-4 proteinase and present evidence that PAPP-A induced cleavage of IGFBP-4 is potentially a key regulatory step in bone metabolism. We also highlight some recent findings with regard to IGFBP-2 and IGFBP-5 (also PAPP-A substrates) function in bone tissue and briefly discuss the actions of the other three IGFBPs (-1, -3, and -6) in this tissue. Although our main focus will be in bone we will allude to IGFBP activity in other cells and tissues where appropriate.

Regulatory mechanisms involved in muscle and bone remodeling during refeeding in gilthead sea bream

“…So, in a fasting condition, or under severe chronic undernutrition, Igf1 concentrations decrease in association with low bone turnover and significant bone loss 71,72 . In fish, early studies also demonstrated the growth stimulatory effect of Igf1 in branchial arches of Japanese eel (Anguilla japonica) 69 and more recently, in an in vitro model of bone-derived cells from vertebra of gilthead sea bream, Igf1 as well as insulin, were demonstrated to stimulate cell proliferation 70 .…”

“…Information about the effects of fasting and refeeding on bone has been mainly studied in cellular-boned fish, like the rainbow trout 65,66 , while in fish species with acellular bone such as gilthead sea bream knowledge is limited. In mammals, it is well known that Igfs are important mediators of bone growth 67,68 , being present at high concentrations in the bone matrix and, any deficiency on the Igf genes affecting skeletal growth 69 . Igfs stimulate differentiation of osteoblasts regulating the balance between bone accretion and resorption, which occurs throughout life 70 .…”

Transcriptome analysis of growth heterosis in pearl oyster Pinctada fucata martensii

“…The IGFs are a type of multifunctional cell proliferation regulators that play key roles in regulating invertebrate metabolism, growth, and reproduction . As IGFs binding proteins, IGFBPs maintain IGF in the circulation, mediate the regulation of IGF independent activities, and regulate the growth and development of bone and other tissues.…”

Osteoimmunology: The Regulatory Roles of T Lymphocytes in Osteoporosis

“…The pathogenesis of GIO was predominantly attributed to the fact that GCs impaired bone formation by reduction of osteoblast differentiation and activity via the expression of the osteoblast-specific transcription factor runt-related Runx2 ( 95 – 97 ). In addition, the long-term GC administration affects bone remodeling by whittling the insulin-like growth factor (IGF) in ossification ( 98 ). GCs enhanced the expression levels of RANKL in both osteoblasts and stromal cells, which triggered osteoclastogenesis and activated osteoclastic bone resorption by binding to the RANKL receptor RANK ( 99 ), thus resulting in the primary phase of rapid bone loss.…”