Interleukin‐1β induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt‐5a/receptor tyrosine kinase–like orphan receptor 2 pathway

Sonomoto, Koshiro; Yamaoka, Kunihiro; Oshita, Koichi; Fukuyo, Shunsuke; Zhang, Xiangmei; Nakano, Kazuhisa; Okada, Yosuke; Tanaka, Yoshiya

doi:10.1002/art.34555

Cited by 142 publications

(104 citation statements)

References 36 publications

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“…Our conclusion disagrees with that of Sonomoto et al (7), but it is hard to determine possible reasons for this discrepancy because they added IL-1␤ to MSCs in commercial "osteogenic induction medium" that includes dexamethasone and "mesangial cell growth supplement." The presence of dexamethasone would account for the induction of ALP and mineralization, thus obscuring any direct effect that IL-1␤ might have had.…”

Section: Discussioncontrasting

confidence: 99%

“…This raised the possibility that IL-1␤ induced the differentiation of the hMSCs into osteoblasts. Such a conclusion would agree with the recent paper of Sonomoto et al (7). However, Kuroki et al (9) and Gowen et al (8) reported that IL-1␤ inhibits mineral deposition by human osteoprogenitor cells, and it is well established that IL-1␤ inhibits the differentiation of rodent osteoprogenitor cells into osteoblasts (10 -12).…”

supporting

confidence: 85%

“…Our inhibitor data suggest this is isoform-specific. The paper by Sonomoto et al (7) emphasizes the role of Wnt signaling in MSC responses to IL-1␤, something that was not examined here. These two pathways need not be mutually exclusive; indeed there is growing evidence of Wnt-MAPK synergies in certain cells (31).…”

Section: Discussionmentioning

confidence: 99%

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Inflammatory Cytokines Induce a Unique Mineralizing Phenotype in Mesenchymal Stem Cells Derived from Human Bone Marrow

Ferreira

Porter

Wehling

et al. 2013

Journal of Biological Chemistry

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Background:The effects of inflammation upon the biology of human mesenchymal stem cells are poorly understood. Results: IL-1␤ provoked massive hydroxyapatite deposition by inhibiting ectonucleotide pyrophosphatase. Cells did not express typical markers of osteoblasts or other mesenchymal lineages. Conclusion: Inflammation promotes mineralization by a novel mechanism. Significance: These data provide new insights into cytokine effects on mineralization of soft tissues.

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Section: Discussioncontrasting

confidence: 99%

supporting

confidence: 85%

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Inflammatory Cytokines Induce a Unique Mineralizing Phenotype in Mesenchymal Stem Cells Derived from Human Bone Marrow

Ferreira

Porter

Wehling

et al. 2013

Journal of Biological Chemistry

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“…We hypothesize that Wnt5a stimulates TNAP and mineralization through inhibition of PPAR activity in osteoblasts [25,30]. More importantly, we also report that Wnt5a blockade decreased basal TNAP activity indicating that Wnt5a is a constitutive autocrine activator of mineralization [34,41]. Wnt5a may therefore represent a possible target to block ossification in AS.…”

Section: Discussionsupporting

confidence: 55%

“…Moreover, we hypothesize that endogenous Dkk1 levels also inhibited the increase in b-catenin protein levels in response to TNF-a (Fig. 3B) and IL-1b (data not shown and [34]). Interestingly, in addition to Wnt10b levels, Dkk1 levels were increased by TNF-a in MSCs (Fig.…”

Section: Canonical Wnt Signaling Is Not Involved In the Stimulation Omentioning

confidence: 86%

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Briolay

Lencel²,

Bessueille

et al. 2013

Biochemical and Biophysical Research Communications

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a b s t r a c tAlthough anti-tumor necrosis factor (TNF)-a treatments efficiently block inflammation in ankylosing spondylitis (AS), they are inefficient to prevent excessive bone formation. In AS, ossification seems more prone to develop in sites where inflammation has resolved following anti-TNF therapy, suggesting that TNF-a indirectly stimulates ossification. In this context, our objectives were to determine and compare the involvement of Wnt proteins, which are potent growth factors of bone formation, in the effects of TNF-a on osteoblast function. In human mesenchymal stem cells (MSCs), TNF-a significantly increased the levels of Wnt10b and Wnt5a. Associated with this effect, TNF-a stimulated tissue-non specific alkaline phosphatase (TNAP) and mineralization. This effect was mimicked by activation of the canonical bcatenin pathway with either anti-Dkk1 antibodies, lithium chloride (LiCl) or SB216763. TNF-a reduced, and activation of b-catenin had little effect on expression of osteocalcin, a late marker of osteoblast differentiation. Surprisingly, TNF-a failed to stabilize b-catenin and Dkk1 did not inhibit TNF-a effects. In fact, Dkk1 expression was also enhanced in response to TNF-a, perhaps explaining why canonical signaling by Wnt10b was not activated by TNF-a. However, we found that Wnt5a also stimulated TNAP in MSCs cultured in osteogenic conditions, and increased the levels of inflammatory markers such as COX-2. Interestingly, treatment with anti-Wnt5a antibodies reduced endogenous TNAP expression and activity. Collectively, these data suggest that increased levels of Dkk1 may blunt the autocrine effects of Wnt10b, but not that of Wnt5a, acting through non-canonical signaling. Thus, Wnt5a may be potentially involved in the effects of inflammation on bone formation.

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Contribution of the Interleukin‐6/STAT‐3 Signaling Pathway to Chondrogenic Differentiation of Human Mesenchymal Stem Cells

Kondo¹,

Yamaoka

Sakata³

et al. 2015

Arthritis & Rheumatology

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Objective. Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into chondrocytes. Articular cartilage contains MSC-like chondroprogenitor cells, which suggests their involvement in the maintenance of cartilage homeostasis by a self-repair mechanism. Interleukin-6 (IL-6) is a cytokine with a wide range of physiologic functions, which are produced by MSCs in a steady manner and in large quantities. The purpose of this study was to investigate the involvement of IL-6 signaling in MSC differentiation into chondrocytes.Methods. Human bone marrow-derived MSCs were cultured using a pellet culture system in medium containing transforming growth factor b3. Chondrogenic differentiation was detected by cartilage matrix accumulation and chondrogenic marker gene expression.Results. IL-6 was detected at a high concentration in culture supernatants during chondrogenic differentiation. The expression of the IL-6 receptor (IL-6R) was significantly increased, accompanied by markedly increased phosphorylation and expression of STAT-3. Addition of IL-6 and soluble IL-6R (sIL-6R) to the chondrogenic culture resulted in concentration-dependent increases in cartilage matrix accumulation and cartilage marker gene expression (type II collagen/aggrecan/type X collagen). Phosphorylation of the master transcription factor SOX9 was enhanced upon addition of IL-6 and sIL-6R. STAT-3 knockdown suppressed chondrogenic differentiation. IL-6 and the MSC markers CD166 and nestin were colocalized in macroscopically normal human cartilage taken from the lateral femoral compartment of knees with medial tibiofemoral osteoarthritis.Conclusion. During differentiation of human MSCs into chondrocytes, the activation of IL-6/STAT-3 signaling positively regulated chondrogenic differentiation. The presence of IL-6 around MSC-like cells in the cartilage tissue was identified, suggesting that IL-6 contributes to homeostasis and cartilage self-repair by promoting chondrogenic differentiation.Articular cartilage is a structurally unique tissue, lacking blood, lymph vessels, and nerves, and it is considered to be in a low-nutrient, low-oxygen environment because of its dependency on nutrient and oxygen supplies primarily from the synovial fluid. Chondrocytes scattered in the cartilage matrix show virtually no proliferative capacity, and it has not been fully elucidated how homeostasis of cartilage tissue is maintained (1). Cartilage was once considered to consist of

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Interleukin‐1β induces differentiation of human mesenchymal stem cells into osteoblasts via the Wnt‐5a/receptor tyrosine kinase–like orphan receptor 2 pathway

Cited by 142 publications

References 36 publications

Inflammatory Cytokines Induce a Unique Mineralizing Phenotype in Mesenchymal Stem Cells Derived from Human Bone Marrow

Inflammatory Cytokines Induce a Unique Mineralizing Phenotype in Mesenchymal Stem Cells Derived from Human Bone Marrow

Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human mesenchymal stem cells

Contribution of the Interleukin‐6/STAT‐3 Signaling Pathway to Chondrogenic Differentiation of Human Mesenchymal Stem Cells

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