Abstract
Aging is a substantial risk factor for the development of osteoarthritis (OA) and, probably, an essential substrate for the development of neoplastic disease of the bone, such as osteosarcoma, which is the most common malignant mesenchymal primary bone tumor. Genetic studies have established that the insulin/insulin-like growth factor 1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT (Protein Kinase B) signal transduction pathway is involved across species, including nematodes, fruit flies, and mammals. SIRT1, a phylogenetically-conserved family of deacetylases, seems to play pleiotropic effects in epithelial malignancies of the liver and interact with the IGF-1/PI3K/AKT signal transduction pathway. Some of the most critical processes in degenerative conditions may indeed include the insulin/IGF1R and SIRT1 signaling pathways as well as some specific transcription factors. The Forkhead box O (FOXO) transcription factors (FOXOs) control diverse cellular functions, such as metabolism, longevity, and cell death. FOXOs play a critical role in the IGF-1/PI3K/AKT signal transduction pathway. FOXOs can indeed be modulated to reduce age-related diseases. FOXOs have advantageous inhibitory effects on fibroblast and myofibroblast activation, which are accompanied by a subsequent excessive production of extracellular matrix. FOXOs can block or decrease the fibrosis levels in numerous organs. Previously, we observed a correlation between nuclear FOXO3 and high caspase-8 expression, which induces cellular apoptosis in response to harmful external stimuli. In this perspective, we emphasize the current advances and interactions involving the insulin/IGF1R, SIRT1, and FOXOs pathways in the bone and osteosarcoma for a better understanding of the mechanisms potentially underpinning tissue degeneration and tumorigenesis.
Highlights
Aging is a substantial risk factor for the development of inflammatory conditions, such as osteoarthritis (OA) and, probably, other degenerative, and neoplastic diseases of the bone, such as Paget disease of the bone and osteosarcoma [1, 2]
We review the insulin/IGF1R, SIRT1, and Forkhead box O (FOXO) signaling pathways and emphasize the interaction involving these crucial factors in the bone physiology and oncogenesis, with
Insulin/IGF-1 receptor (IGF-1R), SIRT1, and FOXOs Pathways regard to osteosarcoma, which is considered the most common mesenchymal malignant primary tumor of the skeletal system
Summary
Aging is a substantial risk factor for the development of inflammatory conditions, such as osteoarthritis (OA) and, probably, other degenerative, and neoplastic diseases of the bone, such as Paget disease of the bone and osteosarcoma [1, 2]. JNKs were initially discovered as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 (two serine amino acid residues) within its transcriptional activation domain [29, 30] They are a member of the mitogen-activated protein kinase (MAPK) family and are responsive to stress stimuli. Following translation of the mRNA into proteins, and no cellular survival initiative of growth factors, FOXOs translocate to the nucleus upregulating a series of target genes of the cell cycle, stress resistance, and longevity. Different from most common transcription regulators, such as extracellular signal-regulated kinase (ERK), which are located in the cytoplasm where kinases are phosphorylated and translocated into the nucleus, FOXOs are transcription factors with a nuclear location. FOXO factors play a crucial role in cell fate decision
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