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

Autor: Fuente R; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland.; Division of Pediatrics, University of Oviedo, Oviedo, Spain., Gehring N; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland., Bettoni C; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland., Gil-Peña H; Division of Pediatrics, University of Oviedo, Oviedo, Spain., Alonso-Durán L; Division of Pediatrics, University of Oviedo, Oviedo, Spain., Michalke B; Department of Environmental Science, Research Unit Analytical, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany., Santos F; Division of Pediatrics, University of Oviedo, Oviedo, Spain.; Department of Pediatrics, Hospital Universitario Central de Asturias, Oviedo, Spain., Wagner CA; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland., Rubio-Aliaga I; Institute of Physiology, University of Zurich, Zurich, Switzerland.; National Center of Competence in Research NCCR Kidney.CH, Zurich, Switzerland.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2021 Jul; Vol. 35 (7), pp. e21721.
DOI: 10.1096/fj.202100587R
Abstrakt: 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.
(© 2021 Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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