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Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes.

ABSTRACT: Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we use the Dmp1Cre:Socs3f/f mouse, with delayed cortical bone consolidation, to characterise cortical maturation and identify control signals. We show that cortical maturation requires a reduction in cortical porosity, and a transition from low to high density bone, which continues even after cortical shape is established. Both processes were delayed in Dmp1Cre:Socs3f/f mice. SOCS3 (suppressor of cytokine signalling 3) inhibits signalling by leptin, G-CSF, and IL-6 family cytokines (gp130). In Dmp1Cre:Socs3f/f bone, STAT3 phosphorylation was prolonged in response to gp130-signalling cytokines, but not G-CSF or leptin. Deletion of gp130 in Dmp1Cre:Socs3f/f mice suppressed STAT3 phosphorylation in osteocytes and osteoclastic resorption within cortical bone, leading to rescue of the corticalisation defect, and restoration of compromised bone strength. We conclude that cortical bone development includes both pore closure and accumulation of high density bone, and that these processes require suppression of gp130-STAT3 signalling in osteocytes.

SUBMITTER: Walker EC

PROVIDER: S-EPMC7253175 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes.

Walker Emma C EC Truong Kim K McGregor Narelle E NE Poulton Ingrid J IJ Isojima Tsuyoshi T Gooi Jonathan H JH Martin T John TJ Sims Natalie A NA

eLife 20200527

Bone strength is determined by its dense cortical shell, generated by unknown mechanisms. Here we use the Dmp1Cre:Socs3f/f mouse, with delayed cortical bone consolidation, to characterise cortical maturation and identify control signals. We show that cortical maturation requires a reduction in cortical porosity, and a transition from low to high density bone, which continues even after cortical shape is established. Both processes were delayed in Dmp1Cre</sup ...[more]

PMID: 32458800

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Project description:IntroductionBone marrow transplantation (BMT) is a complex process regulated by different cytokines and growth factors. The pleiotropic cytokine IL-6 (Interleukin-6) and related cytokines of the same family acting on the common signal transducer gp130 are known to play a key role in bone marrow (BM) engraftment. In contrast, the exact signalling events that control IL-6/gp130-driven haematopoietic stem cell development during BMT remain unresolved.MethodsConditional gp130 knockout and knockin mice were used to delete gp130 expression (gp130(?Mx)), or to selectively disrupt gp130-dependent Ras (gp130(?MxRas)) or STAT signalling (gp130(?MxSTAT)) in BM cells. BM derived from the respective strains was transplanted into irradiated wildtype hosts and repopulation of various haematopoietic lineages was monitored by flow cytometry.ResultsBM derived from gp130 deficient donor mice (gp130(?Mx)) displayed a delayed engraftment, as evidenced by reduced total white blood cells (WBC), marked thrombocytopenia and anaemia in the early phase after BMT. Lineage analysis unravelled a restricted development of CD4(+) and CD8(+) T-cells, CD19(+) B-cells and CD11b(+) myeloid cells after transplantation of gp130-deficient BM grafts. To further delineate the two major gp130-induced signalling cascades, Ras-MAPK and STAT1/3-signalling respectively, we used gp130(?MxRas) and gp130(?MxSTAT) donor BM. BMT of gp130(?MxSTAT) cells significantly impaired engraftment of CD4(+), CD8(+), CD19(+) and CD11b(+) cells, whereas gp130(?MxRas) BM displayed a selective impairment in early thrombopoiesis. Importantly, gp130-STAT1/3 signalling deficiency in BM grafts severely impaired survival of transplanted mice, thus demonstrating a pivotal role for this pathway in BM graft survival and function.ConclusionOur data unravel a vital function of IL-6/gp130-STAT1/3 signals for BM engraftment and haematopoiesis, as well as for host survival after transplantation. STAT1/3 and ras-dependent pathways thereby exert distinct functions on individual bone-marrow-lineages.

Dataset Information

Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes.

Publications

Cortical bone maturation in mice requires SOCS3 suppression of gp130/STAT3 signalling in osteocytes.

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