TGFβ Inducible Early Gene-1 Plays an Important Role in Mediating Estrogen Signaling in the Skeleton

Hawse, John R.; Pitel, Kevin S.; Cicek, Muzaffer; Philbrick, Kenneth A.; Gingery, Anne; Peters, K.D.; Syed, Farhan; Ingle, James N.; Suman, Vera J.; Iwaniec, Urszula T.; Turner, Russell T.; Spelsberg, Thomas C.; Subramaniam, Malayannan

doi:10.1002/jbmr.2142

Cited by 18 publications

(24 citation statements)

References 55 publications

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“…Ovx results in a reduction in cortical thickness in mice that is preventable by oestrogen replacement (Hawse, et al 2014). In the present study, cortical thickness was increased in hypogonadal ob/ob mice following leptin treatment when compared to untreated ob/ob mice but cortical thickness was not restored to WT levels.…”

Section: Discussionmentioning

confidence: 99%

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

Turner

Philbrick

Kuah

et al. 2017

Journal of Endocrinology

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Leptin, critical in regulation of energy metabolism, is also important for normal bone growth, maturation and turnover. Compared to wild type (WT) mice, bone mass is lower in leptin-deficient ob/ob mice; osteopenia in growing ob/ob mice is due to decreased bone accrual, and is associated with reduced longitudinal bone growth, impaired cancellous bone maturation and increased marrow adipose tissue (MAT). However, leptin deficiency also results in gonadal dysfunction, disrupting production of gonadal hormones which regulate bone growth and turnover. The present study evaluated the role of increased oestrogen in mediating the effects of leptin on bone in ob/ob mice. Three-month-old female ob/ob mice were randomized into one of 3 groups: (1) ob/ob+vehicle (veh), (2) ob/ob+leptin (leptin), or (3) ob/ob+leptin and the potent oestrogen receptor antagonist ICI 182,780 (leptin+ICI). Age-matched WT mice received vehicle. Leptin (40 μg/mouse, daily) and ICI (10 μg/mouse, 2x/w) were administered by sc injection for 1 month and bone analyzed by x-ray absorptiometry, microcomputed tomography, and static and dynamic histomorphometry. Uterine weight did not differ between ob/ob mice and ob/ob mice receiving leptin+ICI, indicating that ICI successfully blocked the uterine response to leptin-induced increases in oestrogen levels. Compared to leptin-treated ob/ob mice, ob/ob mice receiving leptin+ICI had lower uterine weight, did not differ in weight loss, MAT, or bone formation rate, and had higher longitudinal bone growth rate and cancellous bone volume fraction. We conclude that increased oestrogen signaling following leptin treatment is dispensable for the positive actions of leptin on bone and may attenuate leptin-induced bone growth.

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Section: Discussionmentioning

confidence: 99%

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

Turner

Philbrick

Kuah

et al. 2017

Journal of Endocrinology

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“…TGFβ inducible early gene‐1 (TIEG), also known as KLF10, was originally cloned from human osteoblasts by our laboratory (Subramaniam et al, 1995). TIEG is a member of the family of Krüppel‐like zinc finger transcription factors and plays an important role in bone homeostasis (Bensamoun et al, 2006b; Hawse et al, 2008; Hawse et al, 2011; Hawse et al, 2014; Subramaniam et al, 1995; Subramaniam et al, 2005; Subramaniam, Pitel, Withers, Drissi, & Hawse, 2016). TIEG misregulation and mutation is known to be correlated with human bone disorders, such as osteoporosis (Hopwood, Tsykin, Findlay, & Fazzalari, 2009; Yerges et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Sclerostin antibody treatment rescues the osteopenic bone phenotype of TGFβ inducible early gene‐1 knockout female mice

Gingery

Subramaniam

Pitel

et al. 2020

Journal Cellular Physiology

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Deletion of TGFβ inducible early gene‐1 (TIEG) in mice results in an osteopenic phenotype that exists only in female animals. Molecular analyses on female TIEG knockout (KO) mouse bones identified increased expression of sclerostin, an effect that was confirmed at the protein level in serum. Sclerostin antibody (Scl‐Ab) therapy has been shown to elicit bone beneficial effects in multiple animal model systems and human clinical trials. For these reasons, we hypothesized that Scl‐Ab therapy would reverse the low bone mass phenotype of female TIEG KO mice. In this study, wildtype (WT) and TIEG KO female mice were randomized to either vehicle control (Veh, n = 12/group) or Scl‐Ab therapy (10 mg/kg, 1×/wk, s.c.; n = 12/group) and treated for 6 weeks. Following treatment, bone imaging analyses revealed that Scl‐Ab therapy significantly increased cancellous and cortical bone in the femur of both WT and TIEG KO mice. Similar effects also occurred in the vertebra of both WT and TIEG KO animals. Additionally, histomorphometric analyses revealed that Scl‐Ab therapy resulted in increased osteoblast perimeter/bone perimeter in both WT and TIEG KO animals, with a concomitant increase in P1NP, a serum marker of bone formation. In contrast, osteoclast perimeter/bone perimeter and CTX‐1 serum levels were unaffected by Scl‐Ab therapy, irrespective of mouse genotype. Overall, our findings demonstrate that Scl‐Ab therapy elicits potent bone‐forming effects in both WT and TIEG KO mice and effectively increases bone mass in female TIEG KO mice.

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“…We have previously demonstrated that global TIEG KO mice exhibit a female specific osteopenic bone phenotype as well as a muted skeletal response to OVX and ERT (Hawse et al, ; Hawse et al, ). Further, sclerostin mRNA and protein are known to be elevated in post‐menopausal women (Mirza, Padhi, Raisz, & Lorenzo, ), sclerostin expression exhibits an inverse relationship with free estrogen index (Drake & Khosla, ) and its expression decreases in response to short term ERT (Modder et al, ).…”

Section: Resultsmentioning

confidence: 99%

TIEG and estrogen modulate SOST expression in the murine skeleton

Subramaniam

Pitel

Bruinsma

et al. 2017

Journal Cellular Physiology

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TIEG knockout (KO) mice exhibit a female-specific osteopenic phenotype and altered expression of TIEG in humans is associated with osteoporosis. Gene expression profiling studies identified sclerostin as one of the most highly up-regulated transcripts in the long bones of TIEG KO mice relative to WT littermates suggesting that TIEG may regulate SOST expression. TIEG was shown to substantially suppress SOST promoter activity and the regulatory elements through which TIEG functions were identified using promoter deletion and chromatin immunoprecipitation assays. Knockdown of TIEG in IDG-SW3 osteocyte cells using shRNA and CRISPR-Cas9 technology resulted in increased SOST expression and delayed mineralization, mimicking the results obtained from TIEG KO mouse bones. Given that TIEG is an estrogen regulated gene, and as changes in the hormonal milieu affect SOST expression, we performed ovariectomy (OVX) and estrogen replacement therapy (ERT) studies in WT and TIEG KO mice followed by miRNA and mRNA sequencing of cortical and trabecular compartments of femurs. SOST expression levels were considerably higher in cortical bone compared to trabecular bone. In cortical bone, SOST expression was increased following OVX only in WT mice and was suppressed following ERT in both genotypes. In contrast, SOST expression in trabecular bone was decreased following OVX and significantly increased following ERT. Interestingly, a number of miRNAs that are predicted to target sclerostin exhibited inverse expression levels in response to OVX and ERT. These data implicate important roles for TIEG and estrogen-regulated miRNAs in modulating SOST expression in bone.

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TGFβ Inducible Early Gene-1 Plays an Important Role in Mediating Estrogen Signaling in the Skeleton

Cited by 18 publications

References 55 publications

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

Role of estrogen receptor signaling in skeletal response to leptin in female ob/ob mice

Sclerostin antibody treatment rescues the osteopenic bone phenotype of TGFβ inducible early gene‐1 knockout female mice

TIEG and estrogen modulate SOST expression in the murine skeleton

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