Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene

Sumana Posritong, Jung Min Hong, Pierre P. Eleniste, Patrick W. McIntyre, Jennifer L. Wu, Evan R. Himes, Vruti Patel, Melissa Kacena, Angela Bruzzaniti

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17β-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor α (ERα), but not estrogen receptor β (ERβ). As a consequence, E2 signaling via ERβ was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERα and ERβ signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases.

Original languageEnglish (US)
JournalMolecular and Cellular Endocrinology
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Focal Adhesion Kinase 2
Osteoblasts
Estrogens
Bone
Estrogen Receptors
Bone and Bones
Osteoclasts
Selective Estrogen Receptor Modulators
Osteogenesis
Tyrosine Kinase 2 Deficiency
Raloxifene Hydrochloride
Postmenopausal Osteoporosis
Bone Remodeling
Bone Diseases
Phosphorylation
Proteasome Endopeptidase Complex
Menopause
Bone Density
Alkaline Phosphatase
Cell Differentiation

Keywords

  • Bone formation
  • Estrogen receptor
  • Mineralization
  • Osteoblast
  • Pyk2
  • SERMs

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Cite this

Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene. / Posritong, Sumana; Hong, Jung Min; Eleniste, Pierre P.; McIntyre, Patrick W.; Wu, Jennifer L.; Himes, Evan R.; Patel, Vruti; Kacena, Melissa; Bruzzaniti, Angela.

In: Molecular and Cellular Endocrinology, 01.01.2018.

Research output: Contribution to journalArticle

Posritong, Sumana ; Hong, Jung Min ; Eleniste, Pierre P. ; McIntyre, Patrick W. ; Wu, Jennifer L. ; Himes, Evan R. ; Patel, Vruti ; Kacena, Melissa ; Bruzzaniti, Angela. / Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene. In: Molecular and Cellular Endocrinology. 2018.
@article{5758857d7bac4173bf2d0a5f63f3c009,
title = "Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene",
abstract = "Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17β-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor α (ERα), but not estrogen receptor β (ERβ). As a consequence, E2 signaling via ERβ was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERα and ERβ signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases.",
keywords = "Bone formation, Estrogen receptor, Mineralization, Osteoblast, Pyk2, SERMs",
author = "Sumana Posritong and Hong, {Jung Min} and Eleniste, {Pierre P.} and McIntyre, {Patrick W.} and Wu, {Jennifer L.} and Himes, {Evan R.} and Vruti Patel and Melissa Kacena and Angela Bruzzaniti",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.mce.2018.02.005",
language = "English (US)",
journal = "Molecular and Cellular Endocrinology",
issn = "0303-7207",
publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Pyk2 deficiency potentiates osteoblast differentiation and mineralizing activity in response to estrogen or raloxifene

AU - Posritong, Sumana

AU - Hong, Jung Min

AU - Eleniste, Pierre P.

AU - McIntyre, Patrick W.

AU - Wu, Jennifer L.

AU - Himes, Evan R.

AU - Patel, Vruti

AU - Kacena, Melissa

AU - Bruzzaniti, Angela

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17β-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor α (ERα), but not estrogen receptor β (ERβ). As a consequence, E2 signaling via ERβ was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERα and ERβ signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases.

AB - Bone remodeling is controlled by the actions of bone-degrading osteoclasts and bone-forming osteoblasts (OBs). Aging and loss of estrogen after menopause affects bone mass and quality. Estrogen therapy, including selective estrogen receptor modulators (SERMs), can prevent bone loss and increase bone mineral density in post-menopausal women. Although investigations of the effects of estrogen on osteoclast activity are well advanced, the mechanism of action of estrogen on OBs is still unclear. The proline-rich tyrosine kinase 2 (Pyk2) is important for bone formation and female mice lacking Pyk2 (Pyk2-KO) exhibit elevated bone mass, increased bone formation rate and reduced osteoclast activity. Therefore, in the current study, we examined the role of estrogen signaling on the mechanism of action of Pyk2 in OBs. As expected, Pyk2-KO OBs showed significantly higher proliferation, matrix formation, and mineralization than WT OBs. In addition we found that Pyk2-KO OBs cultured in the presence of either 17β-estradiol (E2) or raloxifene, a SERM used for the treatment of post-menopausal osteoporosis, showed a further robust increase in alkaline phosphatase (ALP) activity and mineralization. We examined the possible mechanism of action and found that Pyk2 deletion promotes the proteasome-mediated degradation of estrogen receptor α (ERα), but not estrogen receptor β (ERβ). As a consequence, E2 signaling via ERβ was enhanced in Pyk2-KO OBs. In addition, we found that Pyk2 deletion and E2 stimulation had an additive effect on ERK phosphorylation, which is known to stimulate cell differentiation and survival. Our findings suggest that in the absence of Pyk2, estrogen exerts an osteogenic effect on OBs through altered ERα and ERβ signaling. Thus, targeting Pyk2, in combination with estrogen or raloxifene, may be a novel strategy for the prevention and/or treatment of bone loss diseases.

KW - Bone formation

KW - Estrogen receptor

KW - Mineralization

KW - Osteoblast

KW - Pyk2

KW - SERMs

UR - http://www.scopus.com/inward/record.url?scp=85042158671&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042158671&partnerID=8YFLogxK

U2 - 10.1016/j.mce.2018.02.005

DO - 10.1016/j.mce.2018.02.005

M3 - Article

C2 - 29428397

AN - SCOPUS:85042158671

JO - Molecular and Cellular Endocrinology

JF - Molecular and Cellular Endocrinology

SN - 0303-7207

ER -