Load Regulates Bone Formation and Sclerostin Expression through a TGFβ-Dependent Mechanism

Nguyen, Jacqueline; Tang, Simon Y.; Nguyen, Daniel H.; Alliston, Tamara

doi:10.1371/journal.pone.0053813

Cited by 73 publications

(86 citation statements)

References 45 publications

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“…5D) in three-dimensional cultures (p Ͻ 0.001 for all) upon PTH treatment. Previous reports have demonstrated that TGF␤ 1 increases SOST/sclerostin levels during mechanical loading (47,48). In contrast to prior reports, treatment of Ocy454 cells with TGF␤ 1 (10 ng/ml; 24 h) resulted in a down-regulation of SOST (Fig.…”

Section: Three-dimensional Culture Enhances Osteocytic Phenotype-mentioning

confidence: 62%

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro

Spatz

Wein

Gooi

et al. 2015

Journal of Biological Chemistry

257

261

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Background: Recent studies have suggested osteocytes as key players in mechanosensation and skeletal metabolism. Results: Simulated microgravity induces an autonomous up-regulation of SOST/sclerostin and RANKL/OPG in a novel osteocytic cell line, Ocy454. Conclusion: Mechanical loading regulates intrinsic osteocyte responses in concert with hormonal and cytokine inputs. Significance: Learning how osteocytes sense mechanical loads would enable novel interventions to prevent disuse-induced bone loss.

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Section: Three-dimensional Culture Enhances Osteocytic Phenotype-mentioning

confidence: 62%

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro

Spatz

Wein

Gooi

et al. 2015

Journal of Biological Chemistry

257

261

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“…Expression of osteocalcin ( Oc ) and bone sialoprotein ( Ibsp ), Dmp1 and Phex genes that control systemic mineral homeostasis was unaffected by the absence of osteocytic TGFβ signaling. Expression of Sost, which is known to be induced by TGFβ (Loots et al, 2012; Nguyen et al, 2013), was downregulated in TβRII ocy−/− bones (Fig. 3G).…”

Section: Resultsmentioning

confidence: 96%

Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling

et al. 2017

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Summary Poor bone quality contributes to bone fragility in diabetes, aging, and osteogenesis imperfecta. However, the mechanisms controlling bone quality are not well understood, contributing to the current lack of strategies to diagnose or treat bone quality deficits. TGFβ signaling is a crucial mechanism known to regulate the material quality of bone, but its cellular target in this regulation is unknown. Studies showing that osteocytes directly remodel their perilacunar/canalicular matrix led us to hypothesize that TGFβ controls bone quality through perilacunar/canalicular remodeling (PLR). Using inhibitors and mice with an osteocyte-intrinsic defect in TGFβ signaling (TβRIIocy−/−), we show that TGFβ regulates PLR in a cell-intrinsic manner to control bone quality. Altogether, this study emphasizes that osteocytes are key in executing the biological control of bone quality through PLR, thereby highlighting the fundamental role of osteocyte mediated perilacunar/canalicular remodeling in bone homeostasis and fragility.

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“…The localisation and expression of sclerostin in SFx region can provide some insight into its role for initiating healing. Transforming growth factor-beta 1 (TGF-β) a cytokine expressed abundantly in bone that stimulates matrix protein synthesis and can also influence cells that are responsible for bone modelling and remodelling 25. In this study, our first aim was to determine whether osteocyte apoptosis, linked to the initiation of SFx, was spatially associated with sclerostin and TGF-β protein expression during the early phase of SFx healing.…”

Section: Introductionmentioning

confidence: 99%

Osteocyte expression of caspase-3, COX-2, IL-6 and sclerostin are spatially and temporally associated following stress fracture initiation

Wu¹,

Kidd

Cowling

et al. 2014

BoneKEy Reports

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Stress fractures (SFxs) are debilitating injuries and exact mechanisms that initiate their repair incompletely understood. We hypothesised that osteocyte apoptosis and expression of cytokines and proteins such as sclerostin, VEGF, TGF-β, COX-2 and IL-6 were early signalling events to facilitate the formation of periosteal woven bone and recruitment of osteoclast precursors to the site of remodelling. A SFx was created in the right ulna of mature female wistar rats using cyclic end loading. Rats were killed 1, 4 and 7 days after loading (n=5 per group). Standard histological staining was used to examine SFx morphology and immunohistochemistry to detect the localisation of these proteins and in situ hybridisation to detect mRNA along the SFx line or gene expression to quantify the target genes. Unloaded ulnae served as controls. The labelling index of caspase-3, COX-2 and IL-6 was significantly elevated in the region of SFxs at all time points compared with controls (P<0.001). In addition, the labelling index of sclerostin protein was significantly reduced in osteocytes adjacent to the SFx region when compared with controls at all three time points (P<0.001). Both VEGF and TGF-β expressions were only localised in the woven bone. These data reinforce the involvement of osteocyte apoptosis in the healing of fatigue damage in bone, and demonstrate that local regulation of sclerostin, COX-2 and IL-6 are important signalling events associated with new bone formation and SFx remodelling.

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Load Regulates Bone Formation and Sclerostin Expression through a TGFβ-Dependent Mechanism

Cited by 73 publications

References 45 publications

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro

Osteocyte-Intrinsic TGF-β Signaling Regulates Bone Quality through Perilacunar/Canalicular Remodeling

Osteocyte expression of caspase-3, COX-2, IL-6 and sclerostin are spatially and temporally associated following stress fracture initiation

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