Effects of insulin-like growth factor binding proteins in bone—a matter of cell and site

Abstract

The actions of the insulin-like growth factor (IGF)-system are controlled by six IGF-binding proteins (IGFBPs). The IGFBPs are thought to affect local effects of IGF-I and IGF-II due to higher affinity if compared to IGF-I receptors and due to cell-type specific IGFBP expression patterns. It was found in IGFBP knockout models that the IGFBP family is functionally redundant. Thus, functional analysis of potential effects of IGFBPs is dependent on descriptive studies and models of IGFBP overexposure in vitro and in vivo. In the literature, the role of the IGFBPs for bone growth is highly controversial and, to date, no systematic look has been taken at IGFBPs resolving functional aspects of IGFBPs at levels of cell types and specific locations within bones. Since IGFBPs are thought to represent local modulators of the IGF actions and also exert IGF-independent effects, this approach is particularly reasonable on a physiological level. By sorting the huge number of in part controversial results on IGFBP effects in bone present in the literature for distinct cell types and bone sites it is possible to generate a focused, more specific and a less controversial picture of IGFBP functions in bone.

Contrasting bone effects of temporary versus permanent IGFBP administration in rodents

“…However, IGFBPs have not only IGF-dependent negative effects, which might be related to the inhibitory effects in vivo, but also IGF-independent effects in bone cells, which have been reviewed very recently [2]. Both IGF-dependent and -independent mechanisms contribute to cell type specific effects of IGFBPs, which were also reviewed recently [3,4]. Local expression of IGFBPs, IGF-dependent and -independent effects, posttranslational modifications and degradation by IGFBP-proteases concert an almost inextricable complexity of conditional effects [2,5].…”

The IGF/IGFBP system in relation to macroscopic bone architecture in pediatric renal transplant patients

“…The association in this complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. The liver is the principal source of circulating IGF-I, IGFBP-3, and ALS, but IGF-I is expressed by all nonhepatic tissues, where it has a paracrine/autocrine action [13].…”

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

“…The expression level of these BPs changes with differentiation of the cells [66]. The impact of these BPs on the action of IGF on bone is quite complex, varying according to the BP being evaluated, the molar ratio with IGF, type and differentiation level of cell being evaluated, effect of matrix, posttranscriptional modification, and proteolytic processing [66].…”

“…Osteoprogenitor cells express all six of the high affinity IGF-binding proteins (IGFBP or BP), and chondrocytes express all but BP-1 [66]. The expression level of these BPs changes with differentiation of the cells [66].…”

“…However, proteases such as pregnancy associated plasma protein A (PAPP-A) are also expressed in bone and by cleaving BP-4 can release the bound IGF, promoting bone formation [73]. BP-5 is the most abundant BP in both bone and cartilage [66]. Transgenic overexpression of BP-5 results in a gender specific (males more than females) and site specific (periosteal, not endosteal) reduction in bone formation [74,75], although subcutaneous injection of BP-5 over bone increased trabecular bone formation in ovariectomized mice [76].…”