Insulin-Like Growth Factor Binding Protein 5: A Novel Regulator of Early Osteogenic Differentiation of hMSCs

Abstract

Insulin-like growth factor binding protein 5 (IGFBP5) is broadly bioactive, but its role in osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hMSCs) remains to be clarified. Herein, we determined that IGFBP5 expression was markedly increased during the early osteogenic differentiation of hMSCs. We then overexpressed and knocked down this gene in hMSCs and evaluated the impact of the manipulation of IGFBP5 expression on osteogenic differentiation based upon functional assays, ALP staining, and the expression of osteogenic markers. Together, these analyses revealed that IGFBP5 overexpression enhanced early osteogenic differentiation as evidenced by increased ALP staining and osteogenic marker induction, whereas knocking down this gene impaired the osteogenic process. Overexpressing IGFBP5 also markedly bolstered extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation level, while IGFBP5 knockdown suppressed this signaling activity. We additionally compared the impact of simultaneous IGFBP5 overexpression and ERK1/2 inhibitor treatment to the effect of IGFBP5 overexpression alone in these hMSCs, revealing that small molecule-mediated EKR1/2 inhibition was sufficient to impair osteogenic differentiation in the context of elevated IGFBP5 levels. These findings indicated that IGFBP5 drives the early osteogenic differentiation of hMSCs via the ERK1/2 signaling pathway. Our results offer value as a foundation for future efforts to study and treat serious bone-related diseases including osteoporosis.

Digital spatial profiling of human parathyroid tumors reveals cellular and molecular alterations linked to vitamin D deficiency

“…TOX2 ( TOX high-mobility group box family 2 ) is a transcriptional coactivator that modulates multiple pathways including tissue remodeling and tumor microenvironment functions ( 48 ). One of the two downregulated genes, IGFBP5 ( insulin-like growth factor binding protein 5 ), is a key regulator of osteogenic differentiation, and agents that antagonize its expression have been shown to promote osteoporosis ( 49 , 50 ).…”

“…The enhanced activity of genes in these pathways could enable features common to all parathyroid adenomas such as higher cell density and other tumor-specific structural changes including disruption of stromal boundaries, epithelial cell polarity, and basement membrane attachment. IGFBP5, a gene downregulated in both Def-Ts and Rep-Ts, is an important stimulator of osteogenic differentiation ( 50 ). Because microRNA-mediated silencing of IGFBP5 has been shown to promote osteoporosis ( 49 ), it is possible that attenuated expression of this gene in parathyroid adenomas could contribute to bone mineral density loss in PHPT in addition to the direct osteoclastic effects of PTH.…”

Myoblast-derived exosomal Prrx2 attenuates osteoporosis via transcriptional regulation of lncRNA-MIR22HG to activate Hippo pathway

“…For example, signal transduction protein IGF-binding protein 5 (IGFBP-5) was identified in C2C12 myoblast-derived exosomes(Guescini et al 2010 ). IGFBP-5 has been demonstrated to induce local bone formation in mouse and rat models (Bauss et al 2001 ) and enhance early osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (Zhang Z. M. et al 2021b ). Besides, heat shock proteins (HSP) 25, 70, and 90 were found to be abundant in C2C12 myoblast-derived exosomes (Guescini et al 2010 ), which are essential for osteogenic differentiation (Shimada et al 2003 ; Zhang et al 2018 ).…”