Insulin-Like Growth Factor I (IGF-1) Ec/Mechano Growth Factor – A Splice Variant of IGF-1 within the Growth Plate

Abstract

Human insulin-like growth factor 1 Ec (IGF-1Ec), also called mechano growth factor (MGF), is a splice variant of insulin-like growth factor 1 (IGF-1), which has been shown in vitro as well as in vivo to induce growth and hypertrophy in mechanically stimulated or damaged muscle. Growth, hypertrophy and responses to mechanical stimulation are important reactions of cartilaginous tissues, especially those in growth plates. Therefore, we wanted to ascertain if MGF is expressed in growth plate cartilage and if it influences proliferation of chondrocytes, as it does in musculoskeletal tissues. MGF expression was analyzed in growth plate and control tissue samples from piglets aged 3 to 6 weeks. Furthermore, growth plate chondrocyte cell culture was used to evaluate the effects of the MGF peptide on proliferation. We showed that MGF is expressed in considerable amounts in the tissues evaluated. We found the MGF peptide to be primarily located in the cytoplasm, and in some instances, it was also found in the nucleus of the cells. Addition of MGF peptides was not associated with growth plate chondrocyte proliferation.

Flow perfusion effects on three-dimensional culture and drug sensitivity of Ewing sarcoma

“…Most experts agree on a mesodermal origin for ES, and Toretsky and coworkers have shown that IGF1 signaling is required to transform EWS-FLI1 + mouse fibroblasts into ES-like cells (27,28). In our study, ES cells responded to perfusion analogously to mesenchymal stem cells (MSCs) and other MSC-derived cells, which have been shown to up-regulate IGF1 (and occasionally IGF-2) following mechanical stimulation (14,15,22). Although it remains to be proven, our data suggest that autocrine release of IGF1 by MSCsmediated by physiological levels of shear force-may be sufficient to aid EWS-FLI-1-driven malignant transformation without the need for additional IGF1 in the serum.…”

“…Recognizing the major importance of biomechanical forces in bone tumors (8), and the possible effects on key molecular targets of ES such as the IGF1/IGF-1R pathway (11,22), we sought to expand upon a well-characterized TE bone tumor model pioneered in our laboratory by inclusion of flow perfusion in this study (13). The use of flow perfusion bioreactors provides mechanical stimulation in the form of flow-derived shear stress, which can be tailored within a physiological range by experimentally regulating flow rate and/or medium viscosity (16)(17)(18).…”

“…These forces might spark nuclear mechanochemical processes that enhance IGF1 promoter recognition by the EWS-FLI1 fusion protein (9,29), and ultimately lead to upregulation of IGF1 as we observed. Investigating this hypothesis would be beneficial not only for ES but also for understanding the mechanisms behind mechanotransductive IGF1 upregulation in other cells of mesodermal origin (14,15,22).…”

Mechano growth factor, a splice variant of IGF-1, promotes neurogenesis in the aging mouse brain

“…A similar role of MGF has been explored in chondrogenesis [13] and differentiation of mesenchymal stromal cells [14]. Recently MGF has been shown to have neuroprotective effects in an ischemic brain model [15] and it had been reported to be markedly more effective than IGF-I [16].…”

Bone muscle crosstalk targets muscle regeneration pathway regulated by core circadian transcriptional repressors DEC1 and DEC2

“…40 In general, animal studies have confirmed cell culture studies and confirmed that MGF is a local tissue repair factor which responds to mechanical demands. 38 In a broader sense, different splice variants of IGF-1 display distinct functions within the myogenic pathway wherein isoform IGF-1Eb stimulates satellite cell activation, while isoform IGF-1Ea promotes myoblast proliferation and differentiation into myotubes. 41 In summary, the above rationale of exercise effects on skeletal muscle suggests several conclusions.…”