Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

Walker, Emma C; Johnson, Rachelle W.; Hu, Yifang; Brennan, Holly J.; Poulton, Ingrid J; Zhang, Jian Guo; Jenkins, Brendan J.; Smyth, Gordon K.; Nicola, Nicos A.; Sims, Natalie A.

doi:10.1074/jbc.m116.748483

Cited by 40 publications

(61 citation statements)

References 89 publications

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“…27,28 However, mouse OSM was recently reported to influence bone turnover in a LIFR-dependent fashion, suggesting that signalling by a low-affinity OSM/gp130/LIFR complex may be sufficient to exert biological effects in some settings. 29,30 Although the structural details of ligand-receptor interaction have been elucidated for other members of the OSM cytokine family (including LIF and IL-6), no highresolution structures of OSM-receptor interaction have been reported. Nevertheless, site-directed mutagenesis of OSM has helped identify several residues that are critical for receptor interaction.…”

Section: Discovery and Ligand-receptor Relationshipsmentioning

confidence: 99%

“…86 OSM can promote osteoblast differentiation from mesenchymal stem cell (MSC) precursors, while simultaneously repressing adipocyte differentiation. 29,30,71,84,[86][87][88][89] OSM produced by human CD14 + monocytes or macrophages can potently enhance osteoblastic differentiation of MSC in a manner dependent on OSMR/gp130-activated STAT3 signalling. 71,88,89 Notably, mouse OSM has been proposed to promote osteogenesis in part via LIFR, despite the low affinity of mouse OSM for the LIFR-gp130 receptor complex.…”

Section: Bone Homoeostasis and Pathologymentioning

confidence: 99%

“…71,88,89 Notably, mouse OSM has been proposed to promote osteogenesis in part via LIFR, despite the low affinity of mouse OSM for the LIFR-gp130 receptor complex. 29,30 Intriguingly, in wild-type mouse osteoblasts stimulated with OSM or LIF, both STAT3 and STAT1 are activated, whereas OSM stimulation of Osmr −/− cells preferentially activates STAT3 signalling and pro-osteogenic gene expression. 29 Given the ability of OSM to influence both osteoblast and osteoclast activity, it is reasonable to predict that dysregulated OSM signalling could be pathogenic.…”

Section: Bone Homoeostasis and Pathologymentioning

confidence: 99%

“…29,30 Intriguingly, in wild-type mouse osteoblasts stimulated with OSM or LIF, both STAT3 and STAT1 are activated, whereas OSM stimulation of Osmr −/− cells preferentially activates STAT3 signalling and pro-osteogenic gene expression. 29 Given the ability of OSM to influence both osteoblast and osteoclast activity, it is reasonable to predict that dysregulated OSM signalling could be pathogenic. Indeed, macrophage-derived OSM was recently shown to promote the development of neurogenic heterotopic ossifications (NHOs; ectopic bone formation in soft tissues surrounding joints after spinal cord trauma).…”

Section: Bone Homoeostasis and Pathologymentioning

confidence: 99%

“…In general, mouse OSM is thought to engage only gp130/OSMR complexes with high affinity . However, mouse OSM was recently reported to influence bone turnover in a LIFR‐dependent fashion, suggesting that signalling by a low‐affinity OSM/gp130/LIFR complex may be sufficient to exert biological effects in some settings . Although the structural details of ligand‐receptor interaction have been elucidated for other members of the OSM cytokine family (including LIF and IL‐6), no high‐resolution structures of OSM‐receptor interaction have been reported.…”

Section: A Brief Introduction To Oncostatin M (Osm)mentioning

confidence: 99%

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The oncostatin M‐stromal cell axis in health and disease

West¹,

Owens

Hegazy

2018

Scand J Immunol

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The field of stromal immunology has risen to prominence in the last decade, fuelled by accumulating evidence that nonhaematopoietic mesenchymal cells are not simply involved in modulating tissue structure, but actively contribute to immune processes. In addition to regulating tissue integrity during homoeostasis, stromal cells are sensitive sensors of inflammatory stimuli produced downstream of tissue injury or infection, and respond by producing a wide variety of chemokines, cytokines and adhesion factors that contribute to immunity and tissue repair. When not appropriately regulated, these same processes can result in inflammatory pathology and organ dysfunction. In this review, we provide a brief overview of stromal immunology, followed by a comprehensive discussion of how the IL-6 family cytokine oncostatin M (OSM) coordinates stromal cell activity in diverse physiological and pathological contexts. We conclude by providing a perspective on the potential clinical value of the OSM-stromal cell axis and how this pathway might be exploited therapeutically.

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Section: Discovery and Ligand-receptor Relationshipsmentioning

confidence: 99%

Section: Bone Homoeostasis and Pathologymentioning

confidence: 99%

Section: Bone Homoeostasis and Pathologymentioning

confidence: 99%

Section: Bone Homoeostasis and Pathologymentioning

confidence: 99%

Section: A Brief Introduction To Oncostatin M (Osm)mentioning

confidence: 99%

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The oncostatin M‐stromal cell axis in health and disease

West¹,

Owens

Hegazy

2018

Scand J Immunol

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STAT3 Hyperactivation Due to SOCS3 Deletion in Murine Osteocytes Accentuates Responses to Exercise- and Load-Induced Bone Formation

McGregor

Walker

Chan

et al. 2020

Journal of Bone and Mineral Research

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Cortical bone develops and changes in response to mechanical load, which is sensed by bone-embedded osteocytes. The bone formation response to load depends on STAT3 intracellular signals, which are upregulated after loading and are subject to negative feedback from Suppressor of Cytokine Signaling 3 (Socs3). Mice with Dmp1Cre-targeted knockout of Socs3 have elevated STAT3 signaling in osteocytes and display delayed cortical bone maturation characterized by impaired accrual of high-density lamellar bone. This study aimed to determine whether these mice exhibit an altered response to mechanical load. The approach used was to test both treadmill running and tibial compression in female Dmp1Cre.Socs3 f/f mice. Treadmill running for 5 days per week from 6 to 11 weeks of age did not change cortical bone mass in control mice, but further delayed cortical bone maturation in Dmp1Cre. Socs3 f/f mice; accrual of high-density bone was suppressed, and cortical thickness was less than in genetically-matched sedentary controls. When strain-matched anabolic tibial loading was tested, both control and Dmp1Cre.Socs3 f/f mice exhibited a significantly greater cortical thickness and periosteal perimeter in loaded tibia compared with the contralateral non-loaded bone. At the site of greatest compressive strain, the loaded Dmp1Cre.Socs3 f/f tibias showed a significantly greater response than controls, indicated by a greater increase in cortical thickness. This was due to a greater bone formation response on both periosteal and endocortical surfaces, including formation of abundant woven bone on the periosteum. This suggests a greater sensitivity to mechanical load in Dmp1Cre.Socs3 f/f bone. In summary, mice with targeted SOCS3 deletion and immature cortical bone have an exaggerated response to both physiological and experimental mechanical loads. We conclude that there is an optimal level of osteocytic response to mechanical load required for cortical bone maturation and that load-induced bone formation may be increased by augmenting STAT3 signaling within osteocytes.

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G-CSF Receptor Deletion Amplifies Cortical Bone Dysfunction in Mice With STAT3 Hyperactivation in Osteocytes

Isojima

Walker

Poulton

et al. 2020

Journal of Bone and Mineral Research

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Bone strength is determined by the structure and composition of its thickened outer shell (cortical bone), yet the mechanisms controlling cortical consolidation are poorly understood. Cortical bone maturation depends on SOCS3-mediated suppression of IL-6 cytokine-induced STAT3 phosphorylation in osteocytes, the cellular network embedded in bone matrix. Because SOCS3 also suppresses granulocyte-colony-stimulating factor receptor (G-CSFR) signaling, we here tested whether global G-CSFR (Csf3r) ablation altereed bone structure in male and female mice lacking SOCS3 in osteocytes, (Dmp1 Cre :Socs3 f/f mice). Dmp1 Cre :Socs3 f/f :Csf3r À/À mice were generated by crossing Dmp1 Cre :Socs3 f/f mice with Csf3r À/À mice. Although G-CSFR is not expressed in osteocytes, Csf3r deletion further delayed cortical consolidation in Dmp1 Cre :Socs3 f/f mice. Micro-CT images revealed extensive, highly porous low-density bone, with little true cortex in the diaphysis, even at 26 weeks of age; including more low-density bone and less high-density bone in Dmp1 Cre :Socs3 f/f :Csf3r À/À mice than controls. By histology, the area where cortical bone would normally be found contained immature compressed trabecular bone in Dmp1 Cre :Socs3 f/f :Csf3r À/À mice and greater than normal levels of intracortical osteoclasts, extensive new woven bone formation, and the presence of more intracortical blood vessels than the already high levels observed in Dmp1 Cre :Socs3 f/f controls. qRT-PCR of cortical bone from Dmp1 Cre :Socs3 f/f :Csf3r À/À mice also showed more than a doubling of mRNA levels for osteoclasts, osteoblasts, RANKL, and angiogenesis markers. The further delay in cortical bone maturation was associated with significantly more phospho-STAT1 and phospho-STAT3-positive osteocytes, and a threefold increase in STAT1 and STAT3 target gene mRNA levels, suggesting G-CSFR deletion further increases STAT signaling beyond that of Dmp1 Cre :Socs3 f/f bone. G-CSFR deficiency therefore promotes STAT1/3 signaling in osteocytes, and when SOCS3 negative feedback is absent, elevated local angiogenesis, bone resorption, and bone formation delays cortical bone consolidation. This points to a critical role of G-CSF in replacing condensed trabecular bone with lamellar bone during cortical bone formation.

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Murine Oncostatin M Acts via Leukemia Inhibitory Factor Receptor to Phosphorylate Signal Transducer and Activator of Transcription 3 (STAT3) but Not STAT1, an Effect That Protects Bone Mass

Cited by 40 publications

References 89 publications

The oncostatin M‐stromal cell axis in health and disease

The oncostatin M‐stromal cell axis in health and disease

STAT3 Hyperactivation Due to SOCS3 Deletion in Murine Osteocytes Accentuates Responses to Exercise- and Load-Induced Bone Formation

G-CSF Receptor Deletion Amplifies Cortical Bone Dysfunction in Mice With STAT3 Hyperactivation in Osteocytes

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