The Soluble Interleukin-6 Receptor Is a Mediator of Hematopoietic and Skeletal Actions of Parathyroid Hormone

Cho, Sun Wook; Pirih, Flávia Q.; Koh, Amy J.; Michalski, Megan N.; Eber, Matthew R.; Ritchie, Kathryn; Sinder, Benjamin P.; Oh, Seo Jin; Al-Dujaili, Saja A.; Lee, Woo Jung; Kozloff, Ken; Danciu, Theodora E.; Wronski, Thomas J.; McCauley, Laurie K.

doi:10.1074/jbc.m112.393363

Cited by 36 publications

(37 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As in human cells, in vitro PTH stimulation increases of production of TGFb1 and IGF-1 by murine osteoblasts (Cho et al, 2013, McCarthy et al, 1989, Pfeilschifter et al, 1995. However, the effects of iPTH treatment on the production of these factors is largely unknown.…”

Section: Ipth Treatment In Mice Expands the Pool Of Murine Bm Tregs Bmentioning

confidence: 99%

See 1 more Smart Citation

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH ‐induced bone anabolism in mice

D’Amelio

Tyagi

et al. 2017

EMBO Reports

View full text Add to dashboard Cite

Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration. iPTH-induced bone anabolism involves CD8+ T cell production of the osteogenic Wnt ligand Wnt10b, induced via yet unknown mechanisms. Here we show that Teriparatide and iPTH cause a ~2-3-fold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents iPTH-induced CD8+ T cell Wnt10b production and bone anabolism. Mechanistically, Treg action on CD8+ T cells promotes binding of NFAT1/2 and SMAD3 complexes to a NFAT/SMADactivated Wnt10b promoter region that stimualtes Wnt10b gene expression in CD8+ T cells.

show abstract

Section: Ipth Treatment In Mice Expands the Pool Of Murine Bm Tregs Bmentioning

confidence: 99%

“…Recently, IGF-1 has been recognized as an additional inducer of Tregs (Anguela, Tafuro et al, 2013, Johannesson, Sattler et al, 2014. Since iPTH increases TGFb and IGF-1 production in bone (Cho, Pirih et al, 2013, McCarthy, Centrella et al, 1989, Pfeilschifter, Laukhuf et al, 1995, it is likely that iPTH may induce and/or expand BM Tregs.…”

Section: Introductionmentioning

confidence: 99%

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH ‐induced bone anabolism in mice

D’Amelio

Tyagi

et al. 2017

EMBO Reports

View full text Add to dashboard Cite

show abstract

“…[170][171][172] One of the factors expressed by cancer cells in response to different stimuli such as TGFb is parathyroid hormone-related protein (PTHrP), which acts in a paracrine manner to induce CCL2, IL-6 and the soluble IL-6 receptor (sIL-6R) in osteoblasts. 159,[173][174][175] A recent study showed that PTHrP induces IL-6 and VEGF-A in osteoblasts to activate CD11b þ /Gr1 þ myeloid cells in the bone marrow and enhance angiogenesis, the expression of matrix remodeling proteases and prostate cancer growth in bone. 176 Furthermore, cyclophosphamide was found to drive a temporal accumulation of myeloid cells in the bone marrow, elevated expression of CCL2 and increased incidence of prostate cancer skeletal metastasis in mice.…”

Section: Molecular Pathways Of Metastasis-promoting Inflammationmentioning

confidence: 99%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

View full text Add to dashboard Cite

On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.

show abstract

“…Several lines of evidence suggest that these skeletal and hematopoietic systems in the bone microenvironment are not only structurally adjacent, but also functionally interactive (1)(2)(3)(4). Maintenance of the hematopoietic stem cell niche and B-lymphocyte differentiation has been attributed to osteoblasts (1,2,5).…”

mentioning

confidence: 99%

“…Collectively, osteal macrophages play novel roles in both skeletal and hematopoietic systems, yet knowledge of their functional capacities is limited. PTH anabolic actions have been linked to cells of the myeloid lineage via osteoblast derived sIL6R and Stat3 phosphorylation of CD11b + cells (4). The purpose of this study was to investigate the role of osteal macrophages in bone remodeling and anabolic actions of PTH in bone.…”

mentioning

confidence: 99%

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone

Cho

Soki

Koh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

158

198

View full text Add to dashboard Cite

Cellular subpopulations in the bone marrow play distinct and unexplored functions in skeletal homeostasis. This study delineated a unique role of osteal macrophages in bone and parathyroid hormone (PTH)-dependent bone anabolism using murine models of targeted myeloid-lineage cell ablation. Depletion of c-fms + myeloid lineage cells [via administration of AP20187 in the macrophage Fas-induced apoptosis (MAFIA) mouse model] reduced cortical and trabecular bone mass and attenuated PTHinduced trabecular bone anabolism, supporting the positive function of macrophages in bone homeostasis. Interestingly, using a clodronate liposome model with targeted depletion of mature phagocytic macrophages an opposite effect was found with increased trabecular bone mass and increased PTH-induced anabolism. Apoptotic cells were more numerous in MAFIA versus clodronate-treated mice and flow cytometric analyses of myeloid lineage cells in the bone marrow showed that MAFIA mice had reduced CD68 + cells, whereas clodronate liposome-treated mice had increased CD68 + and CD163 + cells. Clodronate liposomes increased efferocytosis (clearance of apoptotic cells) and gene expression associated with alternatively activated M2 macrophages as well as expression of genes associated with bone formation including Wnt3a, Wnt10b, and Tgfb1. Taken together, depletion of early lineage macrophages resulted in osteopenia with blunted effects of PTH anabolic actions, whereas depletion of differentiated macrophages promoted apoptotic cell clearance and transformed the bone marrow to an osteogenic environment with enhanced PTH anabolism. These data highlight a unique function for osteal macrophages in skeletal homeostasis.

show abstract

The Soluble Interleukin-6 Receptor Is a Mediator of Hematopoietic and Skeletal Actions of Parathyroid Hormone

Cited by 36 publications

References 51 publications

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH ‐induced bone anabolism in mice

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH ‐induced bone anabolism in mice

Inflammation and skeletal metastasis

Osteal macrophages support physiologic skeletal remodeling and anabolic actions of parathyroid hormone in bone

Contact Info

Product

Resources

About