Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production

Oshita, Koichi; Yamaoka, Kunihiro; Udagawa, Nobuyuki; Fukuyo, Shunsuke; Sonomoto, Koshiro; Maeshima, Keisuke; Kurihara, Ryuji; Nakano, Kazuhisa; Saito, Kazuyoshi; Okada, Yosuke; Chiba, Kenji; Tanaka, Yoshiya

doi:10.1002/art.30309

Cited by 76 publications

(67 citation statements)

References 45 publications

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“…Based on our results and existing literature, the multilineage and T cell suppressive properties seem to be common among MSCs derived from all sources; however, there might be few tissue-specific functions that can be attributed to the variations in their anti-osteoclastogenic effect. Our results are in agreement with two other reports demonstrating the inhibitory effect of human bone marrow MSCs on in vitro osteoclastogenesis mediated through osteoprotegerin, a decoy receptor for RANKL, or through surface expression of CD200 (18,19). Although our ASCs constitutively expressed osteoprotegerin (data not shown), the inhibitory effect of ASC-CM on osteoclast differentiation in the presence of high concentrations of RANKL (200 ng/ml) (data not shown) rules out its complete involvement in the inhibition of osteoclastogenesis.…”

Section: Discussionsupporting

confidence: 94%

“…However, the role of MSCs in protecting skeletal component of arthritis, including pathological bone loss and the bone-resorbing osteoclasts, has not been well studied. Also, earlier studies on the role of MSCs in osteoclast differentiation are conflicting, with both stimulatory (16,17) as well as inhibitory (18,19) effects. Therefore, in the present study, we investigated the effect of MSCs on the differentiation of bone-resorbing osteoclasts and inflammation-induced bone loss in the mouse collagen-induced arthritis (CIA) model.…”

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confidence: 99%

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Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

Garimella

Kour

Piprode

et al. 2015

The Journal of Immunology

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammatory synovitis leading to joint destruction and systemic bone loss. The inflammation-induced bone loss is mediated by increased osteoclast formation and function. Current antirheumatic therapies primarily target suppression of inflammatory cascade with limited or no success in controlling progression of bone destruction. Mesenchymal stem cells (MSCs) by virtue of their tissue repair and immunomodulatory properties have shown promising results in various autoimmune and degenerative diseases. However, the role of MSCs in prevention of bone destruction in RA is not yet understood. In this study, we investigated the effect of adipose-derived MSCs (ASCs) on in vitro formation of bone-resorbing osteoclasts and pathological bone loss in the mouse collagen-induced arthritis (CIA) model of RA. We observed that ASCs significantly inhibited receptor activator of NF-κB ligand (RANKL)–induced osteoclastogenesis in both a contact-dependent and -independent manner. Additionally, ASCs inhibited RANKL-induced osteoclastogenesis in the presence of proinflammatory cytokines such as TNF-α, IL-17, and IL-1β. Furthermore, treatment with ASCs at the onset of CIA significantly reduced clinical symptoms and joint pathology. Interestingly, ASCs protected periarticular and systemic bone loss in CIA mice by maintaining trabecular bone structure. We further observed that treatment with ASCs reduced osteoclast precursors in bone marrow, resulting in decreased osteoclastogenesis. Moreover, ASCs suppressed autoimmune T cell responses and increased the percentages of peripheral regulatory T and B cells. Thus, we provide strong evidence that ASCs ameliorate inflammation-induced systemic bone loss in CIA mice by reducing osteoclast precursors and promoting immune tolerance.

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Section: Discussionsupporting

confidence: 94%

mentioning

confidence: 99%

Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

Garimella

Kour

Piprode

et al. 2015

The Journal of Immunology

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“…23 We show for the first time that hBM-MSC express RANKL and, to a much lower level, RANK, when FGF2 is added to the cells ( figure 1B,C). RANKL, but not RANK, expression depends on ERK1/2 activation by FGF2 ( figure 1D).…”

Section: Discussionmentioning

confidence: 67%

FGF2 induces RANKL gene expression as well as IL1β regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells

et al. 2013

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ObjectiveHuman bone marrow mesenchymal stromal cells (hBM-MSC) are being applied in tissue regeneration and treatment of autoimmune diseases (AD). Their cellular and immunophenotype depend on isolation and culture conditions which may influence their therapeutic application and reflect their in vivo biological functions. We have further characterised the phenotype induced by fibroblast growth factor 2 (FGF2) on healthy donor hBM-MSC focusing on the osteoimmunological markers osteoprotegerin (OPG), receptor activator of nuclear factor kB (RANK), RANK ligand (RANKL) and HLA-DR and their regulation of expression by the inflammatory cytokines IL1β and IFNγ.MethodsRANK, RANKL, OPG and HLA-DR expression in hBM-MSC expanded under specific culture conditions, were measured by RT-PCR and flow cytometry. MAPKs induction by FGF2, IL1β and IFNγ in hBM-MSC was analysed by immunoblotting and RT-PCR.ResultsIn hBM-MSC, OPG expression is constitutive and FGF2 independent. RANKL expression depends on FGF2 and ERK1/2 activation. IL1β and IFNγ activate ERK1/2 but fail to induce RANKL. Only IL1β induces P38MAPK. The previously described HLA-DR induced by FGF2 through ERK1/2 on hBM-MSC, is suppressed by IL1β through inhibition of CIITA transcription. HLA-DR induced by IFNγ is not affected by IL1β in hBM-MSC, but is suppressed in articular chondrocytes and lung fibroblasts.ConclusionsRANKL expression and IL1β regulated MHC-class II, both induced via activation of the ERK1/2 signalling pathway, are specific for progenitor hBM-MSC expanded in the presence of FGF2. HLA-DR regulated by IL1β and ERK1/2 is observed on hBM-MSC during early expansion without FGF2 suggesting previous in vivo acquisition. Stromal progenitor cells with this phenotype could have an osteoimmunological role during bone regeneration.

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“…Osteoporosis, or low bone mineral density (BMD), is the single most important risk factor for fracture in older women (1). Progressive bone destruction in RA involves the abnormal activation of osteoclasts, which is due to interactions with synovial fibroblasts and helper T cells that express the receptor activator nuclear factor-κB ligand (RANKL) (2,3).…”

Section: Introductionmentioning

confidence: 99%

Tea Polyphenols Inhibit Rat Osteoclast Formation and Differentiation

et al. 2012

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Abstract. Matrix metalloproteinases (MMPs) play an important role in degeneration of the matrix associated with bone and cartilage. Regulation of osteoclast activity is essential in the treatment of bone disease, including osteoporosis and rheumatoid arthritis. Polyphenols in green tea, particularly epigallocatechin-3-gallate (EGCG), inhibit MMPs expression and activity. However, the effects of the black tea polyphenol, theaflavin-3,3′-digallate (TFDG), on osteoclast and MMP activity are unknown. Therefore, we examined whether TFDG and EGCG affect MMP activity and osteoclast formation and differentiation in vitro. TFDG or EGCG (10 and 100 μM) was added to cultures of rat osteoclast precursors cells and mature osteoclasts. Numbers of multinucleated osteoclasts and actin rings decreased in polyphenol-treated cultures relative to control cultures. MMP-2 and MMP-9 activities were lower in TFDG-and EGCG-treated rat osteoclast precursor cells than in control cultures. MMP-9 mRNA levels declined significantly in TFDG-treated osteoclasts in comparison to control osteoclasts. TFDG and EGCG inhibited the formation and differentiation of osteoclasts via inhibition of MMPs. TFDG may suppress actin ring formation more effectively than EGCG. Thus, TFDG and EGCG may be suitable agents or lead compounds for the treatment of bone resorption diseases.

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Human mesenchymal stem cells inhibit osteoclastogenesis through osteoprotegerin production

Cited by 76 publications

References 45 publications

Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

Adipose-Derived Mesenchymal Stem Cells Prevent Systemic Bone Loss in Collagen-Induced Arthritis

FGF2 induces RANKL gene expression as well as IL1β regulated MHC class II in human bone marrow-derived mesenchymal progenitor stromal cells

Tea Polyphenols Inhibit Rat Osteoclast Formation and Differentiation

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