A study by Miyakoshi et al. represents the first in vivo demonstration of stimulatory effects of IGFBP-4 on bone.1 In contrast to several previous in vitro studies, these investigators find that systemic, pharmacological doses of IGFBP-4 increase bone cell growth and differentiation.1-4 This discovery may have future implications for geriatric health maintenance as IGFBP-4 levels are elevated in the elderly, particularly those with osteoporosis.5
|Figure 1. IGFBP-4 takes up IGF from IGFBP-3 in circulation and moves it into bone tissue. IGFBP-4 can then be cleaved, thus freeing IGF to stimulate bone cell proliferation and differentiation.
Insulin-like growth factors (IGFs) are produced by many cell types and are intimately involved in myriad growth and metabolic mechanisms. IGFs in circulation are bound with high affinity to IGF binding proteins (IGFBPs), which function to stabilize and regulate IGFs. IGFBPs are themselves tightly regulated by phosphorylation, glycosylation, and proteolysis.2 The majority of IGF is bound to IGFBP-3, the most abundant IGFBP. This complex associates with an acid-labile subunit (ALS), which is present in excess, to form an ~150 kDa ternary structure. ALS restricts the ability of IGF to exit circulation by forming these larger complexes. Other IGF/IGFBP complexes are smaller (~50 kDa) and free to diffuse across the vascular endothelium into target tissues.2,6,7
Although levels of IGFBP-4 relative to IGFBP-3 are very low, IGF binding to all IGFBPs is in equilibrium.2 The IGF/IGFBP binding equilibrium may be shifted away from IGFBP-3 toward IGFBP-4, however, after bolus systemic injections of IGFBP-4. The smaller IGF/IGFBP-4 complexes depart circulation and penetrate bone tissue where IGFBP-4 is proteolytically cleaved to release free IGF.1 In previous in vitro and local in vivo experiments, IGFBP-4 administration was inhibitory toward bone cell growth and differentiation presumably due to the absence of abundant IGF in the circulating 150 kDa pool.1
- Miyakoshi, N. et al. (2001) Endocrinology 142:2641.
- Jones, J.I. & D.R. Clemmons (1995) Endocrine Rev.16:3.
- Mohan, S. et al. (1989) Proc. Natl. Acad. Sci. USA 86:8338.
- Mohan, S. et al. (1995) J. Biol. Chem. 270:20424.
- Qin, X. et al. (1998) J. Biol. Chem. 273:23509.
- Lee, C.Y. & M.M. Rechler (1996) Endocrinology 137:2051.
- Lewitt, M.S. et al. (1994) Endocrinology 134:2404.