Estradiol via estrogen receptor beta inhibits chondrogenesis of mouse vertebral growth plate in vitro

Zeng, Kefeng; Zhang, Hongqi; Chen, Yong; Gao, Qile

doi:10.1007/s00381-015-2973-2

Cited by 8 publications

(4 citation statements)

References 20 publications

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“…Further, we showed that Sox9 down-regulation is critical to cause GP retirement or closure. The factors that down-regulate SOX9 at puberty likely include estrogen signaling, as this pathway is well known to cause pubertal growth arrest and was also shown to control Sox9 expression in chondrocytes in vitro (52)(53)(54)(55). Our findings should thus motivate further research to fully decode the mechanisms driving GP maintenance and closure.…”

Section: Discussionmentioning

confidence: 75%

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

Haseeb

Angelozzi

et al. 2021

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

118

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Cartilage is essential throughout vertebrate life. It starts developing in embryos when osteochondroprogenitor cells commit to chondrogenesis, activate a pancartilaginous program to form cartilaginous skeletal primordia, and also embrace a growth-plate program to drive skeletal growth or an articular program to build permanent joint cartilage. Various forms of cartilage malformation and degeneration diseases afflict humans, but underlying mechanisms are still incompletely understood and treatment options suboptimal. The transcription factor SOX9 is required for embryonic chondrogenesis, but its postnatal roles remain unclear, despite evidence that it is down-regulated in osteoarthritis and heterozygously inactivated in campomelic dysplasia, a severe skeletal dysplasia characterized postnatally by small stature and kyphoscoliosis. Using conditional knockout mice and high-throughput sequencing assays, we show here that SOX9 is required postnatally to prevent growth-plate closure and preosteoarthritic deterioration of articular cartilage. Its deficiency prompts growth-plate chondrocytes at all stages to swiftly reach a terminal/dedifferentiated stage marked by expression of chondrocyte-specific (Mgp) and progenitor-specific (Nt5e and Sox4) genes. Up-regulation of osteogenic genes (Runx2, Sp7, and Postn) and overt osteoblastogenesis quickly ensue. SOX9 deficiency does not perturb the articular program, except in load-bearing regions, where it also provokes chondrocyte-to-osteoblast conversion via a progenitor stage. Pathway analyses support roles for SOX9 in controlling TGFβ and BMP signaling activities during this cell lineage transition. Altogether, these findings deepen our current understanding of the cellular and molecular mechanisms that specifically ensure lifelong growth-plate and articular cartilage vigor by identifying osteogenic plasticity of growth-plate and articular chondrocytes and a SOX9-countered chondrocyte dedifferentiation/osteoblast redifferentiation process.

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Section: Discussionmentioning

confidence: 75%

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

Haseeb

Angelozzi

et al. 2021

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

118

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“…13, cells or explants were serum-starved overnight prior to stimulation. Chondrocyte cultures were supplemented with physiological concentrations estrogen (synthetic; 0.1nM; Sigma-Aldrich, shanghai, China), and with or without estrogen receptor inhibitors-ERαinhibitor MPP 25 (20uM; Sigma-Aldrich, shanghai, China) and ERβ inhibitor PHTPP 26,27 (20uM; Sigma-Aldrich, shanghai, China). Later, recombinant human TGF-β1 (10 ng/mL; Peprotech, shanghai, China) and IL-1β (1 ng/mL; Peprotech, shanghai, China) were added into the culture medium, respectively.…”

Section: Methodsmentioning

confidence: 99%

Estrogen Regulation of the Expression of Pain Factor NGF in Rat Chondrocytes

Shang¹,

Zhang²,

Jin³

et al. 2021

JPR

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Objective: Pain is the main symptom of osteoarthritis (OA). Nerve growth factor (NGF) plays a crucial role in the generation of OA pain. And estrogen-alone used resulted in a sustained joint pain reduction in postmenopausal women. So we aim to find whether estrogen alters chondrocytes' NGF level, affecting OA pain. Methods: Primary chondrocytes and cartilage explants isolated from Sprague Dawley rat knees were cultured with physiological concentrations of estrogen (17β-Estradiol ≥ 98%, E2), Estrogen Receptor α (ERα) inhibitor and stimulants. Then, chondrocytes NGF mRNA expression and protein release were analyzed by a quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) respectively. Additionally, cultures were pre-incubated with MEK-ERK inhibitor to identify the signaling pathway that estrogen alters NGF mRNA and protein levels. Results: We found that chondrocytes NGF expression and release were decreased by E2. E2 also reduced chondrocytes IL-1β-stimulated or TGF-β1-stimulated NGF expression. Phosphorylated extracellular signal-regulated kinasep1/2 (p-ERK1/2) signals were detected stronger than the control group by Western Blotting (WB). When we cultured chondrocytes with PD98059 (MEK-ERK inhibitor, PD), NGF mRNA expression was added to 1.41Ct (2.07±0.1 fold). Conclusion:We showed that E2 reduces chondrocytes NGF expression significantly, even after stimulation by TGF-β1 or IL-1β. MEK-ERK signaling is involved in this process.

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“…Previous studies showed regulation of skeletal growth by ERβ in female (Lindberg et al 2001) but not in male mice (Vidal et al 2000). Furthermore, a recent in vitro study suggested an inhibitory effect of ERβ on chondrocyte proliferation (Zeng et al 2016). Taking all this into account, it is still possible that ERβ activation may have an effect on bone growth.…”

Section: :3mentioning

confidence: 99%

Regulation of bone growth via ligand-specific activation of estrogen receptor alpha

Iravani

Lagerquist

Ohlsson

et al. 2017

Journal of Endocrinology

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Estrogens are well known for their capacity to promote bone maturation and at high doses to induce growth plate closure and thereby stop further growth. High-dose estrogen treatment has therefore been used to limit growth in extremely tall girls. However, recent data suggest that this treatment may have severe side effects, including increased risk of cancer and reduced fertility. We hypothesized that estrogenic effects in bone are mediated via ERα signaling. Twelve-week-old ovariectomized female C57BL/6 mice were subcutaneously injected for 4 weeks with E2 or selective ERα (PPT) or ERβ (DPN) agonists. After killing, tibia and femur lengths were measured, and growth plate morphology was analyzed. E2- and PPT-treated mice had shorter tibiae and femur bones when compared to vehicle-treated controls, whereas animals treated with DPN had similar bone lengths compared to controls. Growth plate height and hypertrophic zone height were reduced in animals treated with E2 or PPT but not in those treated with DPN, supporting that the effect was mediated via ERα. Moreover, PCNA staining revealed suppressed proliferation of chondrocytes in the tibia growth plate in PPT- or E2-treated mice compared to controls. Our data show that estrogenic effects on bone growth and growth plate maturation are mainly mediated via ERα. Our findings may have direct implications for the development of new and more selective treatment modalities of extreme tall stature using selective estrogen receptor modulators that may have low side effects than high-dose E2 treatment.

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Estradiol via estrogen receptor beta inhibits chondrogenesis of mouse vertebral growth plate in vitro

Abstract: Estradiol via estrogen/estrogen receptor β axis inhibits the proliferation and differentiation of VGP chondrocytes, which might give some new insight into the regulatory mechanism of bone development.

Cited by 8 publications

References 20 publications

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

SOX9 keeps growth plates and articular cartilage healthy by inhibiting chondrocyte dedifferentiation/osteoblastic redifferentiation

Estrogen Regulation of the Expression of Pain Factor NGF in Rat Chondrocytes

Regulation of bone growth via ligand-specific activation of estrogen receptor alpha

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