Skeletal Effects of Inducible ER alpha Deletion in Osteocytes in Adult Mice

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11150%2F22%3A10449462" target="_blank" >RIV/00216208:11150/22:10449462 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00179906:_____/22:10449462

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=7kH0-Y6oZb" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=7kH0-Y6oZb</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/jbmr.4644" target="_blank" >10.1002/jbmr.4644</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Skeletal Effects of Inducible ER alpha Deletion in Osteocytes in Adult Mice

Popis výsledku v původním jazyce

Estrogen is known to regulate bone metabolism in both women and men, but substantial gaps remain in our knowledge of estrogen and estrogen receptor alpha (ER alpha) regulation of adult bone metabolism. Studies using global ER alpha-knockout mice were confounded by high circulating sex-steroid levels, and osteocyte/osteoblast-specific ER alpha deletion may be confounded by ER alpha effects on growth versus the adult skeleton. Thus, we developed mice expressing the tamoxifen-inducible CreERT2 in osteocytes using the 8-kilobase (kb) Dmp1 promoter (Dmp1(CreERT2)). These mice were crossed with ER alpha(fl//fl) mice to create ER alpha Delta Ocy mice, permitting inducible osteocyte-specific ER alpha deletion in adulthood. After intermittent tamoxifen treatment of adult 4-month-old mice for 1 month, female, but not male, ER alpha Delta Ocy mice exhibited reduced spine bone volume fraction (BV/TV (-20.1%, p = 0.004) accompanied by decreased trabecular bone formation rate (-18.9%, p = 0.0496) and serum P1NP levels (-38.9%, p = 0.014). Periosteal (+65.6%, p = 0.004) and endocortical (+64.1%, p = 0.003) expansion were higher in ER alpha Delta Ocy mice compared to control (Dmp1(CreERT2)) mice at the tibial diaphysis, reflecting the known effects of estrogen to inhibit periosteal apposition and promote endocortical formation. Increases in Sost (2.1-fold, p = 0.001) messenger RNA (mRNA) levels were observed in trabecular bone at the spine in ER alpha Delta Ocy mice, consistent with previous reports that estrogen deficiency is associated with increased circulating sclerostin as well as bone SOST mRNA levels in humans. Further, the biological consequences of increased Sost expression were reflected in significant overall downregulation in panels of osteoblast and Wnt target genes in osteocyte-enriched bones from ER alpha Delta Ocy mice. These findings thus establish that osteocytic ER alpha is critical for estrogen action in female, but not male, adult bone metabolism. Moreover, the reduction in bone formation accompanied by increased Sost, decreased osteoblast, and decreased Wnt target gene expression in ER alpha Delta Ocy mice provides a direct link in vivo between ER alpha and Wnt signaling. (c) 2022 American Society for Bone and Mineral Research (ASBMR).

Název v anglickém jazyce

Skeletal Effects of Inducible ER alpha Deletion in Osteocytes in Adult Mice

Popis výsledku anglicky

Estrogen is known to regulate bone metabolism in both women and men, but substantial gaps remain in our knowledge of estrogen and estrogen receptor alpha (ER alpha) regulation of adult bone metabolism. Studies using global ER alpha-knockout mice were confounded by high circulating sex-steroid levels, and osteocyte/osteoblast-specific ER alpha deletion may be confounded by ER alpha effects on growth versus the adult skeleton. Thus, we developed mice expressing the tamoxifen-inducible CreERT2 in osteocytes using the 8-kilobase (kb) Dmp1 promoter (Dmp1(CreERT2)). These mice were crossed with ER alpha(fl//fl) mice to create ER alpha Delta Ocy mice, permitting inducible osteocyte-specific ER alpha deletion in adulthood. After intermittent tamoxifen treatment of adult 4-month-old mice for 1 month, female, but not male, ER alpha Delta Ocy mice exhibited reduced spine bone volume fraction (BV/TV (-20.1%, p = 0.004) accompanied by decreased trabecular bone formation rate (-18.9%, p = 0.0496) and serum P1NP levels (-38.9%, p = 0.014). Periosteal (+65.6%, p = 0.004) and endocortical (+64.1%, p = 0.003) expansion were higher in ER alpha Delta Ocy mice compared to control (Dmp1(CreERT2)) mice at the tibial diaphysis, reflecting the known effects of estrogen to inhibit periosteal apposition and promote endocortical formation. Increases in Sost (2.1-fold, p = 0.001) messenger RNA (mRNA) levels were observed in trabecular bone at the spine in ER alpha Delta Ocy mice, consistent with previous reports that estrogen deficiency is associated with increased circulating sclerostin as well as bone SOST mRNA levels in humans. Further, the biological consequences of increased Sost expression were reflected in significant overall downregulation in panels of osteoblast and Wnt target genes in osteocyte-enriched bones from ER alpha Delta Ocy mice. These findings thus establish that osteocytic ER alpha is critical for estrogen action in female, but not male, adult bone metabolism. Moreover, the reduction in bone formation accompanied by increased Sost, decreased osteoblast, and decreased Wnt target gene expression in ER alpha Delta Ocy mice provides a direct link in vivo between ER alpha and Wnt signaling. (c) 2022 American Society for Bone and Mineral Research (ASBMR).

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30202 - Endocrinology and metabolism (including diabetes, hormones)

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Bone and Mineral Research

ISSN

0884-0431

e-ISSN

1523-4681

Svazek periodika

37

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

1750-1760

Kód UT WoS článku

000828895500001

EID výsledku v databázi Scopus

2-s2.0-85134468346