IGF‐1 signaling mediated cell‐specific skeletal mechano‐transduction

Abstract

Mechanical loading preserves bone mass and stimulates bone formation, whereas skeletal unloading leads to bone loss. In addition to osteocytes, which are considered the primary sensor of mechanical load, osteoblasts, and bone specific mesenchymal stem cells also are involved. The skeletal response to mechanical signals is a complex process regulated by multiple signaling pathways including that of insulin-like growth factor-1 (IGF-1). Conditional osteocyte deletion of IGF-1 ablates the osteogenic response to mechanical loading. Similarly, osteocyte IGF-1 receptor (IGF-1R) expression is necessary for reloading-induced periosteal bone formation. Transgenic overexpression of IGF-1 in osteoblasts results in enhanced responsiveness to in vivo mechanical loading in mice, a response which is eliminated by osteoblastic conditional disruption of IGF-1 in vivo. Bone marrow derived stem cells (BMSC) from unloaded bone fail to respond to IGF-1 in vitro. IGF-1R is required for the transduction of a mechanical stimulus to downstream effectors, transduction which is lost when the IGF-1R is deleted. Although the molecular mechanisms are not yet fully elucidated, the IGF signaling pathway and its interactions with potentially interlinked signaling cascades involving integrins, the estrogen receptor, and wnt/β-catenin play an important role in regulating adaptive response of cancer bone cells to mechanical stimuli. In this review, we discuss recent advances investigating how IGF-1 and other interlinked molecules and signaling pathways regulate skeletal mechano-transduction involving different bone cells, providing an overview of the IGF-1 signaling mediated cell-specific response to mechanical stimuli. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:576-583, 2018.

Interactions between Muscle and Bone—Where Physics Meets Biology

“…As expected, the adenosine monophosphate-activated protein kinase (AMPK) that functions as a main signal transduction mechanism for muscle hypertrophy was identified [173]. A putative candidate for the interactive effects on muscle and bone is IGF-1 and the downstream cascade of PI3 kinase/AKT signaling (phosphoinositide 3-kinase/ serine/threonine kinase signaling), which is also regulated by disuse versus exercise [174,175]. Mechanosensitive ion channels, which were discussed above as important generators of calcium spikes for osteogenic signals, are altered in µG as shown for neuronal cells or the cells of primitive organisms.…”

Icariin, but Not Genistein, Exerts Osteogenic and Anti-apoptotic Effects in Osteoblastic Cells by Selective Activation of Non-genomic ERα Signaling

“…As icariin does not bind to ERs, the cellular targets that directly interact with icariin to elicit non-genomic signaling in osteoblastic cells remain unknown. As growth factor (such as IGF-1) plays an important role in bone growth and remodeling ( Guntur and Rosen, 2013 ; Tian et al, 2018 ) and its receptor (IGF1R) is an upstream regulator of both MAPK and PI3K signaling pathways ( Fuentes et al, 2011 ), it is possible that IGF-1 and IGF1R might play a role in mediating the actions of icariin in osteoblastic cells. In particular, just like icariin, IGF-1 is known to induce Akt phosphorylation in osteoblastic cells ( Sunters et al, 2010 ).…”

Strain and Vibration in Mesenchymal Stem Cells

“…Whole body vibration studies have been used to model the cyclic tensile strain imparted on muscle or bone during physical actives such as walking, stair climbing, or weight lifting exercises [ 34 ]. The vibration stimulates the skeleton in a manner similar to walking or running and has been found to increase bone mass and bone strength [ 33 – 35 , 40 ]. Whole body vibration stimulates osteogenesis of MSCs through mechanotransduction, resulting in a bone mass increase [ 35 , 39 ].…”