IL-3 Inhibits Human Osteoclastogenesis and Bone Resorption through Downregulation of c-Fms and Diverts the Cells to Dendritic Cell Lineage

Gupta, Navita; Barhanpurkar, Amruta P.; Tomar, Geetanjali B.; Srivastava, Rupesh K.; Kour, Supinder; Pote, Satish T.; Mishra, Gyan C.; Wani, Mohan R.

doi:10.4049/jimmunol.1000015

Cited by 41 publications

(45 citation statements)

References 58 publications

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“…In addition, they induce expression of MMPs, which degrade cartilage matrix, thereby aggravating the degeneration of joints (15). We have previously shown that IL-3 is a potent inhibitor of osteoclast formation and pathological bone resorption in vitro (17)(18)(19)(20), and it protects cartilage and bone damage in murine models of inflammatory arthritis (20) and collagen-induced arthritis (21). In this study, we investigated the role of IL-3 in regulation of chondrocyte function in vitro and cartilage degradation in vivo in a mouse model of human OA.…”

Section: Discussionmentioning

confidence: 99%

“…The high affinity receptor for IL-3 consists of a heterodimer of IL-3-specific a-chain and a common b-chain, which is shared with GM-CSF and IL-5 (33). IL-3Ra is expressed by human hematopoietic stem cells (34), endothelial cells and monocytes (35), activated T cells (21), osteoclasts (17)(18)(19), osteoblasts, and MSCs (36). In this study, we report for the first time, to our knowledge, that both mouse and human chondrocytes express IL-3Ra at transcript and protein levels.…”

Section: Discussionmentioning

confidence: 99%

“…It is a broadly acting hematopoietic-regulatory protein, which acts on a number of cell lineages including macrophages, mast cells, neutrophils, eosinophils, and megakaryocytes. Previously, we have documented that IL-3 irreversibly inhibits in vitro osteoclast differentiation induced by receptor activator of NF-kB ligand and TNF-a in both mice and human osteoclast precursors and directs the cells to macrophage and dendritic cell lineages (17)(18)(19). We have also shown that IL-3 is a potent inhibitor of pathological bone resorption induced by TNF-a and other proinflammatory cytokines such as IL-1a, TGF-b1, TGF-b3, IL-6, and PGE 2 (20).…”

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confidence: 99%

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IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

Kour

Garimella

Shiroor

et al. 2016

The Journal of Immunology

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Osteoarthritis (OA) is a chronic disease of articular joints that leads to degeneration of both cartilage and subchondral bone. These degenerative changes are further aggravated by proinflammatory cytokines including IL-1β and TNF-α. Previously, we have reported that IL-3, a cytokine secreted by activated T cells, protects cartilage and bone damage in murine models of inflammatory and rheumatoid arthritis. However, how IL-3 protects cartilage degeneration is not yet known. In this study, we investigated the role of IL-3 on cartilage degeneration under both in vitro and in vivo conditions. We found that both mouse and human chondrocytes show strong expression of IL-3R at gene and protein levels. IL-3 increases the expression of mouse chondrocyte-specific genes, Sox9 and collagen type IIa, which were downregulated by IL-1β. Moreover, IL-3 downregulated IL-1β– and TNF-α–induced expression of matrix metalloproteinases in both mouse and human chondrocytes. Interestingly, IL-3 reduces the degeneration of articular cartilage and subchondral bone microarchitecture in a mouse model of human OA. Moreover, IL-3 showed the preventive and therapeutic effects on cartilage degeneration induced by IL-1β in micromass pellet cultures of human mesenchymal stem cells. Thus, to our knowledge, we provide the first evidence that IL-3 has therapeutic potential in amelioration of degeneration of articular cartilage and subchondral bone microarchitecture associated with OA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

Kour

Garimella

Shiroor

et al. 2016

The Journal of Immunology

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“…IL-3 directly inhibited osteoclast differentiation from human peripheral blood monocytes (Gupta et al, 2010). The addition of IL-3 greatly suppressed the expressions of c-Fms, PU.1, and c-Fos.…”

Section: Regulation Of Osteoclast Differentiation By Interleukins Thamentioning

confidence: 92%

The Role of Jak/STAT Pathways in Osteoclast Differentiation

Lee¹,

Kim²

2011

Biomolecules and Therapeutics

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OSTEOCLASTOsteoclasts are the bone-resorbing cells of monocyte/macrophage origin (Boyle et al., 2003). In mice, CD45R -CD11b low bone marrow cells were identifi ed as osteoclast precursors at least in vitro (Jacquin et al., 2006). Mizoguchi et al. established that cell cycle arrest in osteoclast precursors is prerequisite for osteoclast differentiation (Mizoguchi et al., 2009). These cells were identifi ed as c-Fms + (M-CSF receptor) RANKL + cells at the site of osteoclastogenesis in vivo. Upon stimulation of these osteoclast precursors with macrophage colonystimulation factor (M-CSF) and receptor activator of nuclear factor kappa B ligand (RANKL), these cells differentiate and fi nally fuse to form multinuclear functional osteoclasts through a multi-step process. M-CSF supports the survival and proliferation of osteoclast precursors. The critical role of M-CSF in osteoclastogenesis was revealed by the osteopetrotic bone phenotype of op/op mice, which lack functional M-CSF leading to the absence of osteoclasts (Yoshida et al., 1990). Genetic ablation of RANKL also induced osteopetrosis accompanied by complete loss of osteoclasts (Kong et al., 1999). Ligation of RANKL receptor (RANK) by RANKL recruits TNF receptor associated factors (TRAFs) and stimulates NF-κB, c-Fos, and NFATc1-mediated gene transcription by activating multiple signaling cascades including mitogen-activated proOsteoclasts are bone-resorbing cells of monocyte/macrophage origin and are culprits of bone destruction associated with osteoporosis, rheumatoid arthritis, and cancer bone metastasis. Recent advances in osteoclast biology revealed central roles of various cytokines in regulating osteoclastogenesis both in vitro and in vivo. However, exact underlying mechanisms including signaling pathways downstream of receptor ligation are still under pursuit. In the present review, the role of Jak/STAT proteins and their regulators will be discussed in connection with osteoclastogenesis, since growing evidence indicates that a number of cytokines and growth factors utilizing Jak/STAT signaling pathways affect osteoclastogenesis. A better understanding on the role of Jak/ STAT pathways in osteoclast differentiation will not only strengthen our knowledge on osteoclast biology but also provide invaluable insights into the development of anti-resorptive strategies for treating bone-lytic diseases. Abstract tein kinases such as ERK, JNK, and p38 as well as phosphatidylinositol 3-kinase (PI3K)/Akt pathways (Lee and Kim, 2003). The major osteoclast signaling pathway is depicted in Fig.

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“…IL-3 is a known potent inhibitor of mouse osteoclast formation. Very recently we have shown that IL-3 also inhibits human osteoclast formation (8). Thus, IL-3 treatment may increase the percentage of Foxp3…”

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confidence: 96%

Comment on “IL-3 Attenuates Collagen-Induced Arthritis by Modulating the Development of Foxp3+ Regulatory T Cells”

Zhu

et al. 2011

The Journal of Immunology

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IL-3 Inhibits Human Osteoclastogenesis and Bone Resorption through Downregulation of c-Fms and Diverts the Cells to Dendritic Cell Lineage

Cited by 41 publications

References 58 publications

IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

IL-3 Decreases Cartilage Degeneration by Downregulating Matrix Metalloproteinases and Reduces Joint Destruction in Osteoarthritic Mice

The Role of Jak/STAT Pathways in Osteoclast Differentiation

Comment on “IL-3 Attenuates Collagen-Induced Arthritis by Modulating the Development of Foxp3+ Regulatory T Cells”

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