IGF-I Self-modulation in Cultured Growth Plate Chondrocytes
© 2005 Prime Health Consultants, Inc.
Although circulating hormones play an important role in regulating growth in the growth plate, there is an increasing appreciation of the contributions of local factors in fine-tuning the process. Sometimes, the same factor can be both endocrine and autocrine/paracrine. Insulin-like growth factor (IGF)-I is one such factor and is a major stimulus for growth plate chondrocyte proliferation and differentiation. IGF-I bioavailability and hence, activity are determined by the relative concentrations of the IGFs, IGF receptor, IGF binding proteins (IGFBPs), IGFBP proteases and IGF or IGFBP inducers within the cellular microenvironment.
Because IGF-I was found to affect IGFBP synthesis in some tissues, Kiepe and colleagues sought to examine the micro loop between IGF-I and its binding proteins within the growth plate. They used epiphyseal chondrocytes isolated from Sprague-Dawley rats, cultured in monolayers, as their experimental model. In such primary cultures they had previously found exclusive inhibition of IGF-dependent growth by IGFBP-1,-2,-4 and -6, enhancement of IGF-induced proliferation by IGFBP-5 and mixed effects by IGFBP-3; it inhibited chondrocyte proliferation in both IGF-independently and in IGF-coincubation, but enhanced IGF responsiveness when preincubated before IGF treatment.
Under basal conditions, the conditioned media of the primary chondrocyte cultures contained IGFBP-2 through 5. Addition of exogenous IGF-I to the serum-free medium led to a dose- and time-dependent induction of IGFBP-3 and -5 mRNA and protein. Specific inhibitors of the p42/44 MAP kinase or PI3 kinase pathways were used to discern which of its 2 major signaling pathways IGF-I was utilizing for its actions. Under basal conditions, none of the inhibitors affected chondrocyte proliferation nor mRNA expression of either IGFBP-3 or -5. However, during IGF-I treatment, inhibitors of both pathways completely suppressed the stimulated chondrocyte growth and IGFBP-3 expression; IGF-stimulated IGFBP-5 expression was only suppressed by inhibiting the PI3 kinase pathway. A mesenchymal chondrogenic cell line (growth plate chondrocytes derived from fetal rat calvaria) was used to confirm the epiphyseal chondrocyte findings of IGFBP-5 stimulation by IGF-I. This cell line does not express either endogenous IGF-I or IGFBP-3. It, too, showed that IGF-induced IGFBP-5 expression was dependent on the PI3 kinase but not the MAP kinase pathway. Because both actinomycin D and cyclohexamide abolished the IGFBP-5 induction by IGF-I, both transcription and de novo protein synthesis were involved.
Editor’s Comment: Interestingly, in addition to the multiple levels of control of IGF-I bioavailability and action, IGF-I can further modulate itself by affecting local IGFBP levels. IGFBP induction by IGF-I is cell-type specific, as is the pathway(s) IGF-I uses to do so. Besides stimulating IGFBP synthesis, as shown in the paper by Kiepe and colleagues, IGF-I can also induce IGFBP proteolysis. For example, IGF-I can induce IGFBP-3 proteases, which contributes to cancer cell migration and metastasis,1 and has been shown to induce IGFBP-4 proteolysis in fetal lung fibroblasts.2
The IGF system is an integral player in bone biology, not just for growth but also for strength. I refer the reader to reference 3 for an excellent review of the IGF system’s role in determining bone mass. Not surprisingly, perturbations in the IGF system have been implicated in skeletal disease. For example, human osteoarthritic chondrocytes produced more IGF-I than normal chondrocytes, but demonstrated an even greater increase in IGFBP-3 and -5.4 By fully understanding the regulatory balances within the skeletal IGF system, the potential for targeted therapeutic intervention is increased.
Adda Grimberg, MD
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