PuSH - Publication Server of Helmholtz Zentrum München: Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth.

Navigation

Home

Deutsch

Research

Advanced Search

Browse by ...

... Journal

... Publication Type

... Research Data

... Publication Year

Publication overview

Support & Contact

Contact persons

Help

Data protection

Fuente, R.* ; Gehring, N.* ; Bettoni, C.* ; Gil-Pena, H.* ; Alonso-Durán, L.* ; Michalke, B. ; Santos, F.* ; Wagner, C.A.* ; Rubio-Aliaga, I.*

Systemic Jak1 activation causes extrarenal calcitriol production and skeletal alterations provoking stunted growth.

FASEB J. 35:e21721 (2021)

DOI

PMC

Open Access Green as soon as Postprint is submitted to ZB.

Abstract
Metrics
Extra information

Mineral homeostasis is regulated by a complex network involving endocrine actions by calcitriol, parathyroid hormone (PTH), and FGF23 on several organs including kidney, intestine, and bone. Alterations of mineral homeostasis are found in chronic kidney disease and other systemic disorders. The interplay between the immune system and the skeletal system is not fully understood, but cytokines play a major role in modulating calcitriol production and function. One of the main cellular signaling pathways mediating cytokine function is the Janus kinase (JAK)--signal transducer and activator of transcription (STAT) pathway. Here, we used a mouse model (Jak1^S645P+/- ) that resembles a constitutive activating mutation of the Jak1/Stat3 signaling pathway in humans, and shows altered mineral metabolism, with higher fibroblast growth factor 23 (FGF23) levels, lower PTH levels, and higher calcitriol levels. The higher calcitriol levels are probably due to extrarenal calcitriol production. Furthermore, systemic Jak1/Stat3 activation led to growth impairment and skeletal alterations. The growth plate in long bones showed decreased chondrocyte proliferation rates and reduced height of terminal chondrocytes. Furthermore, we demonstrate that Jak1 is also involved in bone remodeling early in life. Jak1^S645P+/- animals have decreased bone and cortical volume, imbalanced bone remodeling, reduced MAP kinase signaling, and local inflammation. In conclusion, Jak1 plays a major role in bone health probably both, directly and systemically by regulating mineral homeostasis. Understanding the role of this signaling pathway will contribute to a better knowledge in bone growth and in mineral physiology, and to the development of selective Jak inhibitors as osteoprotective agents.

Altmetric

Additional Metrics?

[➜Log in]

Edit extra informations Login

Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Jak/stat Signaling ; Bone Mass Density ; Calcitriol ; Growth Plate; Vitamin-d Metabolism; 1,25-dihydroxyvitamin D-3; Marked Alterations; D-receptor; Plate; Expression; Disease; 1-alpha-hydroxylase; Mutation; Pathway

ISSN (print) / ISBN 0892-6638

e-ISSN 1530-6860

Journal FASEB Journal

Quellenangaben Volume: 35, Issue: 7, Article Number: e21721

Publisher Wiley

Publishing Place Bethesda, Md.

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Analytical BioGeoChemistry (BGC)

Grants MINECO | Instituto de Salud Carlos III (ISCIII)