Age-related changes in effects of insulin-like growth factor I on human osteoblast-like cells

d'AVIS, Patricia Y.; Frazier, Chester R.; Shapiro, Jay R.; Fedarko, Neal S.

doi:10.1042/bj3240753

Cited by 47 publications

(11 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Biglycan mRNA levels were also significantly ( p ≤ 0.01) upregulated, as shown by real-time PCR analysis (Figure 2D ). These data are well in accord with previous reports where IGF-I has been shown to regulate the expression of biglycan in human osteoblast-like cells ( 23 ).…”

Section: Resultssupporting

confidence: 94%

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis

et al. 2018

View full text Add to dashboard Cite

Biglycan, a small leucine rich proteoglycan (SLRP), is an important participant in bone homeostasis and development as well as in bone pathology. In the present study biglycan was identified as a positive regulator of MG63 osteosarcoma cell growth (p ≤ 0.001). IGF-I was shown to increase biglycan expression (p ≤ 0.01), whereas biglycan-deficiency attenuated significantly both basal and IGF-I induced cell proliferation of MG63 cells (p ≤ 0.001; p ≤ 0.01, respectively). These effects were executed through the IGF-IR receptor whose activation was strongly attenuated (p ≤ 0.01) in biglycan-deficient MG63 cells. Biglycan, previously shown to regulate Wnt/β-catenin pathway, was demonstrated to induce a significant increase in β-catenin protein expression evident at cytoplasmic (p ≤ 0.01), membrane (p ≤ 0.01), and nucleus fractions in MG63 cells (p ≤ 0.05). As demonstrated by immunofluorescence, increase in β-catenin expression is attributed to co-localization of biglycan with the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) resulting in attenuated β-catenin degradation. Furthermore, applying anti-β-catenin and anti-pIGF-IR antibodies to MG-63 cells demonstrated a cytoplasmic and to the membrane interaction between these molecules that increased upon exogenous biglycan treatment. In parallel, the downregulation of biglycan significantly inhibited both basal and IGF-I-dependent ERK1/2 activation, (p ≤ 0.001). In summary, we report a novel mechanism where biglycan through a LRP6/β-catenin/IGF-IR signaling axis enhances osteosarcoma cell growth.

show abstract

Section: Resultssupporting

confidence: 94%

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis

et al. 2018

View full text Add to dashboard Cite

show abstract

“…With aging, tissue responsiveness to IGF‐1 in general is altered. (11–15) Aging is associated with decreases in IGF‐IR and IGF‐IR phosphorylation in muscle,(12) senescence of heart myocytes is accompanied by a reduction in the phosphorylated form of AKT,(13) and in the liver, insulin receptor substrate (IRS) protein levels decrease, and some, but not all investigators, found reduced levels of IGF‐1R. (14) Fibroblast DNA synthesis and proliferation in response to IGF‐1 decrease with age.…”

Section: Introductionmentioning

confidence: 99%

Aging Impairs IGF-I Receptor Activation and Induces Skeletal Resistance to IGF-I

Cao

Kurimoto

Boudignon

et al. 2007

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

IGF-I plays an important anabolic role in stimulating bone formation and maintaining bone mass. We show that the pro-proliferative, anti-apoptotic, and functional responses to IGF-I in bone and BMSCs decrease with aging. These changes are associated with impaired receptor activation and signal transduction through the MAPK and PI3K pathways.Introduction: IGF-I is a potent anabolic agent having effects across diverse tissues and cell types. With aging, bone becomes resistant to the anabolic actions of IGF-I. To examine the effects of aging on bone responsiveness to IGF-I, we measured the pro-proliferative, anti-apoptotic, and functional responses of bone and bone marrow stromal cells (BMSCs) to IGF-I and evaluated IGF-I signal transduction in young, adult, and old mice. Materials and Methods: Male C57BL/6 mice 6 wk (young), 6 mo (adult), and 24 mo (old) were treated with IGF-I for 2 wk using osmotic minipumps, and osteoblast proliferation (BrdU labeling) in vivo, and osteoprogenitor number (BMSC culture and calcium nodule formation) were measured. Proliferation, apoptosis, and expression of key osteoblast factors (alkaline phosphatase, collagen, osteocalcin, RANKL, osteoprotegerin (OPG), macrophage-colony stimulating factor [M-CSF]) and IGF-I signaling elements and their activation in IGF-I-treated cells were studied using QRT-PCR and Western blot analysis. Data were analyzed using ANOVA. Results: Aging decreased the basal and IGF-I-stimulated number of BrdU-labeled osteoblasts and reduced the ability of IGF-I to stimulate osteoprogenitor formation (calcium nodule number) by 50%. The proproliferative and anti-apoptotic actions of IGF-I were blunted in cells from old animals. These changes were accompanied by age-related alterations in the ability of IGF-I to regulate alkaline phosphatase, collagen, osteocalcin, RANKL, OPG, and M-CSF expression. IGF-I binding was normal, but IGF-I receptor mRNA and protein expression was increased in aged animals by 2-and 10-fold, respectively. The age-related changes in proliferation, apoptosis, and function were accompanied by loss of IGF-I-induced signaling at the receptor level and at key regulatory sites along the MAPK (ERK1/2) and PI3K (AKT) pathways. Conclusions: Our data show that aging is accompanied by loss of bone and BMSC/osteoblast responsiveness to IGF-I and that these changes are associated with resistance to IGF-I signaling that involve receptor activation and downstream signaling events.

show abstract

“…Such is the case for osteoblast response to insulin‐like growth factor‐1 (IGF‐1). IGF‐1 receptor levels do not change, but osteoblast response to the growth factor decreases with age [Pfeilschifter et al, 1993, 2000; D'Avis et al, 1997; Ankrom et al, 1998]. In this way, age‐associated shifts in any given factor could be either further enhanced or ameliorated quite locally [Rosen, 2000].…”

Section: Normal and Aging Bone Stroma: A Rich Soil For Cancer Cellsmentioning

confidence: 99%

Modulation of prostate cancer growth in bone microenvironments

Edlund

Sung

Chung

2003

J of Cellular Biochemistry

View full text Add to dashboard Cite

Bone remains one of the major sites, and most lethal host organs, for prostate cancer metastasis. Prostate cell spread and establishment in bone depends on multiple reciprocal modifications of bone stromal and epithelial cancer cell behaviors. This review focuses on recent advances in the characterization of cell-cell and cell-matrix interplay, effects on cell growth, adhesion and invasion, and several therapeutic possibilities for co-targeting prostate cancer cells and bone stroma. We address the topic from three main perspectives: (1) the normal and aging bone stromal environment, (2) the "reactive" bone stromal environment, and (3) the cancerous prostate epithelial cells themselves. First, normal, and especially aging, bones provide uniquely rich and "fertile soil" for roaming cancer cells. The interactions between prostate cancer cells and insoluble extracellular matrices, soluble growth factors, and/or sex steroid hormones trigger bone remodeling, through increased osteoclastogenesis and furthur matrix metalloproteinase activity. Second, after cancer cell arrival and establishment in the bone, host stromal cells respond, becoming "reactive" in a process again involving extracellular matrix remodeling, together with growth factor and steroid receptor signaling this process ultimately enhances cancer cell migration, stromal transdifferentiation, and invasion of the cancer tissues by stromal, inflammatory, and immune-responsive cells. Third, prostate cancer cells also respond to supportive bone microenvironments, where soluble and matrix-associated molecules affect cancer cell growth and gene expression, especially altering cancer cell surface receptor and integrin-mediated cell signaling. We discuss both integrin cell-matrix and gap junctional cell-cell communication between cancer cells and their microenvironments during prostate cancer progression.

show abstract

Age-related changes in effects of insulin-like growth factor I on human osteoblast-like cells

Cited by 47 publications

References 56 publications

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis

Biglycan Regulates MG63 Osteosarcoma Cell Growth Through a LPR6/β-Catenin/IGFR-IR Signaling Axis

Aging Impairs IGF-I Receptor Activation and Induces Skeletal Resistance to IGF-I

Modulation of prostate cancer growth in bone microenvironments

Contact Info

Product

Resources

About