TY - JOUR
T1 - The role of Zfp467 in mediating the pro-osteogenic and anti-adipogenic effects on bone and bone marrow niche
AU - le, Phuong T.
AU - Liu, Hanghang
AU - Alabdulaaly, Lama
AU - Vegting, Yosta
AU - Calle, Isabella L.
AU - Gori, Francesca
AU - Lanske, Beate
AU - Baron, Roland
AU - Rosen, Clifford J.
N1 - Funding Information: The research reported in this publication was supported by NIH grant R01 DK112374 to Roland Baron and Cliff Rosen. This work utilized services of the Maine Medical Center Research Institute (MMCRI) Molecular Phenotyping Core, which is supported by NIH/NIGMS P30GM106391 , the Histopathology and Histomorphometry Core, which is supported by NIH/NIGMS P30GM106391, P20GM121301, and P30103392, and the Mouse Transgenic and In Vivo Imaging Core which is supported by NIH/NIGMS P30GM103392 . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Terry Henderson and Dorothy Hu for technical assistance. Dr. Lanske current address is: Radius Health Inc., Waltham, MA 02451, USA. Funding Information: Study design: Clifford J. Rosen and Roland Baron. Study conduct: Phuong T. Le and Hanghang Liu. Data collection: Phuong T. Le, Hanghang Liu, Yosta Vegting and Isabella L Calle. Data analysis: Phuong T. Le, Hanghang Liu and Lama Alabdulaaly. Data interpretation: Phuong T. Le, Hanghang Liu, Roland Baron and Clifford J. Rosen. Consulting on experiments: Beate Lanske. Drafting manuscript: Phuong T. Le and Hanghang Liu. Revising manuscript content: Francesca Gori, Roland Baron and Clifford J. Rosen. Approving final version of manuscript: Roland Baron and Clifford J. Rosen. Clifford J. Rosen takes responsibility for the integrity of the data analysis. The research reported in this publication was supported by NIH grant R01 DK112374 to Roland Baron and Cliff Rosen. This work utilized services of the Maine Medical Center Research Institute (MMCRI) Molecular Phenotyping Core, which is supported by NIH/NIGMS P30GM106391, the Histopathology and Histomorphometry Core, which is supported by NIH/NIGMS P30GM106391, P20GM121301, and P30103392, and the Mouse Transgenic and In Vivo Imaging Core which is supported by NIH/NIGMS P30GM103392. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors thank Terry Henderson and Dorothy Hu for technical assistance. Dr. Lanske current address is: Radius Health Inc. Waltham, MA 02451, USA. Publisher Copyright: © 2020 Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Conditional deletion of the PTH receptor (Pth1r) in mesenchymal progenitors reduces osteoblast differentiation and bone mass while enhancing adipogenesis and bone marrow adipose tissue. Mechanistically, PTH suppresses the expression of Zfp467, a pro-adipogenic zinc finger transcription factor. Consequently, Pth1r deficiency in mesenchymal progenitors leads to increased Zfp467 expression. Based on these observations, we hypothesized that genetic loss of Zfp467 would lead to a shift in marrow progenitor cell fate towards osteogenesis and increased bone mass. To test this hypothesis, we generated Zfp467−/− mice. Zfp467−/− mice (−/−) were significantly smaller than Zfp467+/+ mice (+/+). μCT showed significantly higher trabecular bone and cortical bone area in −/− vs. +/+, and histomorphometry showed higher structural and dynamic formation parameters in −/− mice vs. +/+. Femoral gene expression including Alpl, Sp7, and Acp5 were increased in −/−mice, whereas Adiponectin, Cebpa, Lepr, and Ppraγ mRNA were lower in −/− mice. Similarly, Fabp4 and Lep in the inguinal depot were also decreased in −/− mice. Moreover, marrow adipocyte numbers were reduced in −/− vs +/+ mice (p<0.007). In vitro, COBs and BMSCs−/− showed more positive ALP and Alizarin Red staining and a decrease in ORO droplets. Pth1r mRNA and protein levels were increased in COBs and BMSCs from −/− mice vs +/+ (p<0.02 for each parameter, −/− vs. +/+). −/− cells also exhibited enhanced endogenous levels of cAMP vs. control cells. Moreover, in an ovariectomy (OVX) mouse model, Zfp467−/− mice had significantly lower fat mass but similar bone mass compared to OVX +/+ mice. In contrast, in a high fat diet (HFD) mouse model, in addition to reduced adipocyte volume and adipogenesis related gene expression in both peripheral and bone marrow fat tissue, greater osteoblast number and higher osteogenesis related gene expression were also observed in −/− HFD mice vs. +/+ HFD mice. Taken together, these results demonstrate that ZFP467 negatively influences skeletal homeostasis and favors adipogenesis. Global deletion of Zfp467 increases PTHR1, cAMP and bone turnover, hence its repression is a component of PTH signaling and its regulation. These data support a critical role for Zfp467 in early lineage allocation and provide a novel potential mechanism by which PTH acts in an anabolic manner on the bone remodeling unit.
AB - Conditional deletion of the PTH receptor (Pth1r) in mesenchymal progenitors reduces osteoblast differentiation and bone mass while enhancing adipogenesis and bone marrow adipose tissue. Mechanistically, PTH suppresses the expression of Zfp467, a pro-adipogenic zinc finger transcription factor. Consequently, Pth1r deficiency in mesenchymal progenitors leads to increased Zfp467 expression. Based on these observations, we hypothesized that genetic loss of Zfp467 would lead to a shift in marrow progenitor cell fate towards osteogenesis and increased bone mass. To test this hypothesis, we generated Zfp467−/− mice. Zfp467−/− mice (−/−) were significantly smaller than Zfp467+/+ mice (+/+). μCT showed significantly higher trabecular bone and cortical bone area in −/− vs. +/+, and histomorphometry showed higher structural and dynamic formation parameters in −/− mice vs. +/+. Femoral gene expression including Alpl, Sp7, and Acp5 were increased in −/−mice, whereas Adiponectin, Cebpa, Lepr, and Ppraγ mRNA were lower in −/− mice. Similarly, Fabp4 and Lep in the inguinal depot were also decreased in −/− mice. Moreover, marrow adipocyte numbers were reduced in −/− vs +/+ mice (p<0.007). In vitro, COBs and BMSCs−/− showed more positive ALP and Alizarin Red staining and a decrease in ORO droplets. Pth1r mRNA and protein levels were increased in COBs and BMSCs from −/− mice vs +/+ (p<0.02 for each parameter, −/− vs. +/+). −/− cells also exhibited enhanced endogenous levels of cAMP vs. control cells. Moreover, in an ovariectomy (OVX) mouse model, Zfp467−/− mice had significantly lower fat mass but similar bone mass compared to OVX +/+ mice. In contrast, in a high fat diet (HFD) mouse model, in addition to reduced adipocyte volume and adipogenesis related gene expression in both peripheral and bone marrow fat tissue, greater osteoblast number and higher osteogenesis related gene expression were also observed in −/− HFD mice vs. +/+ HFD mice. Taken together, these results demonstrate that ZFP467 negatively influences skeletal homeostasis and favors adipogenesis. Global deletion of Zfp467 increases PTHR1, cAMP and bone turnover, hence its repression is a component of PTH signaling and its regulation. These data support a critical role for Zfp467 in early lineage allocation and provide a novel potential mechanism by which PTH acts in an anabolic manner on the bone remodeling unit.
KW - Bone-fat interactions
KW - Genetic animal models
KW - Osteoblasts
KW - PTH
KW - Stromal/stem cells
UR - http://www.scopus.com/inward/record.url?scp=85098737091&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bone.2020.115832
DO - https://doi.org/10.1016/j.bone.2020.115832
M3 - Article
C2 - 33359894
SN - 8756-3282
VL - 144
JO - Bone
JF - Bone
M1 - 115832
ER -