Role of inflammation in the aging bones

Abdelmagid, Samir M.; Barbe, Mary F.; Safadi, Fayez F.

doi:10.1016/j.lfs.2014.11.011

Cited by 103 publications

(87 citation statements)

References 178 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In parallel, macrophages release TGFβ1 that promotes the proliferation and differentiation of MSCs, thus enhancing processes of bone repair (16, 17). However, the delicate equilibrium between these factors may be impaired in aging individuals by extensive pro-inflammatory processes, whose trigger(s) are not fully identified (6, 18, 19). Our findings raise the possibility that such increased pro-inflammatory phenotype may be gained by the MSCs due to their exposure to TNFα and TGFβ1 simultaneously, at the bone niche.…”

Section: Discussionmentioning

confidence: 99%

“…One such example is the bone, where macrophage-derived TNFα and TGFβ1 induce the migration of MSCs and their differentiation to osteoblasts, thus promoting bone formation (16, 17). Recent findings suggest that reduced bone-forming activities in MSCs are connected to excessive inflammatory conditions that are ensued with increased age, possibly reflecting changes in the microenvironment and its cytokine contents, which may include TNFα and TGFβ1 (6, 18, 19). …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Co-Inflammatory Roles of TGFβ1 in the Presence of TNFα Drive a Pro-inflammatory Fate in Mesenchymal Stem Cells

et al. 2017

View full text Add to dashboard Cite

High plasticity is a hallmark of mesenchymal stem cells (MSCs), and as such, their differentiation and activities may be shaped by factors of their microenvironment. Bones, tumors, and cardiomyopathy are examples of niches and conditions that contain MSCs and are enriched with tumor necrosis factor α (TNFα) and transforming growth factor β1 (TGFβ1). These two cytokines are generally considered as having opposing roles in regulating immunity and inflammation (pro- and anti-inflammatory, respectively). Here, we performed global gene expression analysis of human bone marrow-derived MSCs and identified overlap in half of the transcriptional programs that were modified by TNFα and TGFβ1. The two cytokines elevated the mRNA expression of soluble factors, including mRNAs of pro-inflammatory mediators. Accordingly, the typical pro-inflammatory factor TNFα prominently induced the protein expression levels of the pro-inflammatory mediators CCL2, CXCL8 (IL-8), and cyclooxygenase-2 (Cox-2) in MSCs, through the NF-κB/p65 pathway. In parallel, TGFβ1 did not elevate CXCL8 protein levels and induced the protein expression of CCL2 at much lower levels than TNFα; yet, TGFβ1 readily induced Cox-2 and acted predominantly via the Smad3 pathway. Interestingly, combined stimulation of MSCs by TNFα + TGFβ1 led to a cooperative induction of all three inflammatory mediators, indicating that TGFβ1 functioned as a co-inflammatory cytokine in the presence of TNFα. The cooperative activities of TNFα + TGFβ1 that have led to CCL2 and CXCL8 induction were almost exclusively dependent on p65 activation and were not regulated by Smad3 or by the upstream regulator TGFβ-activated kinase 1 (TAK1). In contrast, the TNFα + TGFβ1-induced cooperative elevation in Cox-2 was mostly dependent on Smad3 (demonstrating cooperativity with activated NF-κB) and was partly regulated by TAK1. Studies with MSCs activated by TNFα + TGFβ1 revealed that they release factors that can affect other cells in their microenvironment and induce breast tumor cell elongation, migration, and scattering out of spheroid tumor masses. Thus, our findings demonstrate a TNFα + TGFβ1-driven pro-inflammatory fate in MSCs, identify specific molecular mechanisms involved, and propose that TNFα + TGFβ1-stimulated MSCs influence the tumor niche. These observations suggest key roles for the microenvironment in regulating MSC functions, which in turn may affect different health-related conditions.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Co-Inflammatory Roles of TGFβ1 in the Presence of TNFα Drive a Pro-inflammatory Fate in Mesenchymal Stem Cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…284 ). Pro-inflammatory cytokines — including IL-1β, IL-6, IL-11, IL-15, IL-17, and TNF — stimulate bone resorption and almost certainly contribute to osteoporosis 285 . For example, bone resorption is increased in patients with inflammatory diseases, such as rheumatoid arthritis 286 .…”

Section: Inflammageing Is a Pillar Of Gerosciencementioning

confidence: 99%

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

2018

View full text Add to dashboard Cite

Most older individuals develop inflammageing, a condition characterized by elevated levels of blood inflammatory markers that carries high susceptibility to chronic morbidity, disability, frailty, and premature death. Potential mechanisms of inflammageing include genetic susceptibility, central obesity, increased gut permeability, changes to microbiota composition, cellular senescence, NLRP3 inflammasome activation, oxidative stress caused by dysfunctional mitochondria, immune cell dysregulation, and chronic infections. Inflammageing is a risk factor for cardiovascular diseases (CVDs), and clinical trials suggest that this association is causal. Inflammageing is also a risk factor for chronic kidney disease, diabetes mellitus, cancer, depression, dementia, and sarcopenia, but whether modulating inflammation beneficially affects the clinical course of non-CVD health problems is controversial. This uncertainty is an important issue to address because older patients with CVD are often affected by multimorbidity and frailty — which affect clinical manifestations, prognosis, and response to treatment — and are associated with inflammation by mechanisms similar to those in CVD. The hypothesis that inflammation affects CVD, multimorbidity, and frailty by inhibiting growth factors, increasing catabolism, and interfering with homeostatic signalling is supported by mechanistic studies but requires confirmation in humans. Whether early modulation of inflammageing prevents or delays the onset of cardiovascular frailty should be tested in clinical trials.

show abstract

“…Serum levels of proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor α (TNF-α), are continuously elevated in the elderly and are associated with many chronic diseases in aging, particularly the differentiation disorders of MSCs (Pawelec et al 2014;Abdelmagid et al 2015). Human aging is generally accompanied by the chronic inflammatory state, termed "inflammaging" (Pawelec et al 2014).…”

Section: Systemic and Local Environmental Changes In Organismal Agingmentioning

confidence: 99%

Microenvironmental Views on Mesenchymal Stem Cell Differentiation in Aging

Sui

Zheng

et al. 2016

J Dent Res

View full text Add to dashboard Cite

Aging is characterized by common environmental changes, such as hormonal, immunologic, and metabolic disorders. These pathologic factors impair the capability of mesenchymal stem cells (MSCs) to generate and maintain functionalized tissue components, contributing to age-related tissue degeneration (e.g., osteoporosis). However, in organismal aging, whether the microenvironmental signals induce common or differential MSC compromise and how they interact at the molecular level in mediating the functional decline of MSCs are not fully understood. In this review, we discuss the respective contribution of microenvironmental pathologic factors to age-related MSC dysfunction-particularly, the shifted differentiation from osteoblasts to adipocytes of bone marrow-derived MSCs. The authors summarize recent works regarding mechanisms underlying MSC-biased differentiation under altered microenvironments, which involve the activation of key signaling pathways, intracellular oxidative stress, and posttranscriptional regulations. In addition, we compare the differential influences of systemic and local microenvironments on MSC differentiation based on our findings. The authors also propose strategies to rescue differentiation disorders of MSCs in aging via modulating microenvironments, by using signaling modulators, anti-inflammatory agents, antioxidants, and metabolic regulators and by promoting mobilization of systemic MSCs to local injury sites. The authors hope that these insights contribute to MSC-based organismal aging research and treatments.

show abstract

Role of inflammation in the aging bones

Cited by 103 publications

References 178 publications

Co-Inflammatory Roles of TGFβ1 in the Presence of TNFα Drive a Pro-inflammatory Fate in Mesenchymal Stem Cells

Co-Inflammatory Roles of TGFβ1 in the Presence of TNFα Drive a Pro-inflammatory Fate in Mesenchymal Stem Cells

Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty

Microenvironmental Views on Mesenchymal Stem Cell Differentiation in Aging

Contact Info

Product

Resources

About