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Differential effects of insulin-like growth factor binding proteins-1, -2, -3, and -6 on cultured growth plate
Daniela Kiepe1, Tim Ulinski, David R Powell
1Division of Pediatric Nephrology, University Children's Hospital, Heidelberg, Germany.
Insights
Insulin-like growth factor binding proteins (IGFBPs) impact growth in children with chronic renal failure. IGFBP-1, -2, and -6 inhibit chondrocyte proliferation, while IGFBP-3
Area of Science:
- Endocrinology
- Pediatric Nephrology
- Cell Biology
Background:
- Children with chronic renal failure (CRF) often experience impaired longitudinal growth.
- Excessive insulin-like growth factor binding proteins (IGFBPs) may interfere with insulin-like growth factor (IGF) signaling, impacting growth.
- Different IGFBPs may have contrasting effects on longitudinal growth.
Purpose of the Study:
- To investigate the biological effects of IGFBP-1, -2, -3, and -6 on growth plate chondrocytes.
- To understand the role of IGFBPs in modulating longitudinal growth in pediatric CRF.
Main Methods:
- Primary rat growth plate chondrocytes were cultured.
- Proliferation was assessed using colony formation and [3H]thymidine assays.
- IGFBP binding to chondrocytes and IGF-I binding were evaluated.
Main Results:
- IGFBP-1, IGFBP-2, and IGFBP-6 inhibited IGF-stimulated DNA synthesis and proliferation.
- IGFBP-3 exhibited complex effects: inhibiting proliferation independently and dependently on IGF, but enhancing IGF-I responsiveness under preincubation conditions.
- IGFBP-3 facilitates IGF-I binding to the cell membrane.
Conclusions:
- IGFBP-1, IGFBP-2, and IGFBP-6 act as growth inhibitors on chondrocyte proliferation.
- IGFBP-3 can either inhibit or enhance chondrocyte proliferation and IGF responsiveness, depending on its temporal relationship with IGF exposure.
- Findings highlight the differential roles of IGFBPs in regulating chondrocyte function and longitudinal growth.
Background:
In children with chronic renal failure (CRF), impairment of longitudinal growth is in part due to excess amounts of circulating high-affinity insulin-like growth factor binding proteins (IGFBPs) that might decrease or prevent insulin-like growth factor (IGF) binding to its signaling receptor. However, it appears from the clinical studies that various IGFBPs may have contrasting effects on longitudinal growth. Because of the potential importance of the IGFBPs as modulators of longitudinal growth in pediatric CRF, the aim of the present study was to investigate the biological effects of IGFBP-1, -2, -3, and -6 on cultured growth plate chondrocytes that express the type 1 IGF receptor.
Methods:
The effects of exogenous IGFBPs on IGF-independent and IGF-dependent proliferation of rat growth plate chondrocytes in primary culture were investigated. Proliferation was assessed by colony formation of agarose-stabilized long-term suspension cultures and by the [3H]thymidine assay. The effects of IGFBPs on IGF-I binding and the binding of IGFBPs to chondrocytes were assessed by binding studies with radiolabeled proteins in monolayer culture.
Results:
Intact IGFBP-1, IGFBP-2 and IGFBP-6 inhibited in equimolar concentration the IGF-I- and IGF-II-stimulated DNA synthesis and cell proliferation, whereas the biological activity of IGFBP-3 was complex. It had an IGF-independent antiproliferative effect and also inhibited IGF-dependent chondrocyte proliferation under coincubation conditions, whereas under preincubation conditions IGFBP-3 enhanced IGF-I-responsiveness. Studies on the mechanism by which IGFBP-3 potentiated IGF activity demonstrated that under preincubation conditions IGFBP-3 is capable to associate with the cell membrane and to facilitate IGF-I cell surface binding.
Conclusions:
Intact IGFBP-1, IGFBP-2 and IGFBP-6 act exclusively as growth inhibitors on IGF-dependent proliferation of growth plate chondrocytes. IGFBP-3, however, can either inhibit IGF-independent and IGF-dependent cell proliferation, or enhance IGF responsiveness of chondrocytes dependent on the temporal relationship to the IGF exposure.
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