Abstract
The IGF axis is represented by two growth factors (IGF1 and IGF2), two cognate cell surface receptors (IGF1R and IGF2R), six soluble high affinity IGF binding proteins (IGFBP1-6) and several IGFBP proteases. IGF1 and IGF2 are present at high concentrations in bone and play a crucial role in the maintenance and differentiation of both foetal and adult skeleton. In order to understand the role of the IGF axis in bone and other tissues it is necessary to profile the expression and activity of all genes in the axis together with the activity of relevant ancillary proteins (including IGFBP proteases). In the current report we used differentiating human dental pulp cells (hDPC) to examine the expression and activity of the IGF axis during osteogenic differentiation of these cells. We found that, with the exception of IGF1 and IGFBP1, all components of the IGF axis are expressed in hDPCs. IGFBP-4 is the most abundantly expressed IGFBP species at both mRNA and protein levels under both basal and osteogenic conditions. Although we found no difference in IGFBP-4 expression under osteogenic conditions, we report increased expression and activity of pregnancy associated plasma protein-A (PAPP-A - an IGFBP-4 proteinase) leading to increased IGFBP-4 proteolysis in differentiating cell cultures. Further to this we report increased expression of IGF-2 (an activator of PAPP-A), and decreased expression of stanniocalcin-2 (STC2- a recently discovered inhibitor of PAPP-A) under osteogenic conditions. We also demonstrate that STC2 and PAPP-A are able to form complexes in hDPC conditioned medium indicating the potential for regulation of IGFBP-4 proteolysis through this mechanism. We suggest that these changes in the expression and activity of the IGF axis may represent part of an osteogenic signature characteristic of differentiating hDPCs.
Highlights
The insulin-like growth factor (IGF) axis comprises two polypeptide growth factors (IGF1 and IGF2), two cell surface receptors (IGF1R and IGF2R) and six soluble high-affinity IGF binding proteins (IGFBP-1-6)
We have recently shown that insulin-like growth factor binding protein (IGFBP)-2 enhanced and IGFBP-3 inhibited the pro-osteogenic effects of IGF1 in human dental pulp cells (hDPC)
The expression of IGFBP-4 and IGFBP-5 did not change during hDPC differentiation (Fig. 1b and c), but as these IGFBPs are 10–100 fold more abundant than IGFBP-2 or IGFBP-3 (Fig. 1a and c), we investigated the effect of IGFBP-4 and IGFBP-5 on the osteogenic activity of IGF1
Summary
The insulin-like growth factor (IGF) axis comprises two polypeptide growth factors (IGF1 and IGF2), two cell surface receptors (IGF1R and IGF2R) and six soluble high-affinity IGF binding proteins (IGFBP-1-6). The IGF axis plays a crucial role in the development and maintenance of the mineralised skeleton and disruption of the IGF1 or IGF1R gene compromises skeletal growth in rodents and humans [1, 2]. IGFs are the most abundant growth factors in bone tissue [3] and in addition to an anabolic role in mature bone, the IGF axis regulates osteoblast and osteoclast differentiation in developing bone tissue, controlling the balance between bone accretion and resorption which occurs throughout life [4,5,6]. Conditional knockout of IGF1 or IGF1R in osteoblasts or mature osteocytes compromises bone development and impairs osteogenic differentiation of mesenchymal stem cells [7, 8].
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