SHIP1 deficiency causes inflammation-dependent retardation in skeletal growth

Author:

Safari Fatemeh123ORCID,Yeoh Wen Jie24ORCID,Perret-Gentil Saskia1,Klenke Frank5,Dolder Silvia1,Hofstetter Willy16ORCID,Krebs Philippe4ORCID

Affiliation:

1. Bone & Joint Program, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland

2. Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland

3. AO Research Institute Davos, Davos, Switzerland

4. Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland

5. Department of Orthopaedic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland

6. Department of Cranio-Maxillofacial Surgery, Inselspital, Bern University Hospital, Bern, Switzerland

Abstract

Inflammation and skeletal homeostasis are closely intertwined. Inflammatory diseases are associated with local and systemic bone loss, and post-menopausal osteoporosis is linked to low-level chronic inflammation. Phosphoinositide-3-kinase signalling is a pivotal pathway modulating immune responses and controlling skeletal health. Mice deficient in Src homology 2–containing inositol phosphatase 1 (SHIP1), a negative regulator of the phosphoinositide-3-kinase pathway, develop systemic inflammation associated with low body weight, reduced bone mass, and changes in bone microarchitecture. To elucidate the specific role of the immune system in skeletal development, a genetic approach was used to characterise the contribution of SHIP1-controlled systemic inflammation to SHIP1-dependent osteoclastogenesis. Lymphocyte deletion entirely rescued the skeletal phenotype inRag2−/−/Il2rg−/−/SHIP1−/−mice.Rag2−/−/Il2rg−/−/SHIP1−/−osteoclasts, however, displayed an intermediate transcriptomic signature between control andRag2+/+/Il2rg+/+/SHIP1−/−osteoclasts while exhibiting aberrant in vitro development and functions similar toRag2+/+/Il2rg+/+/SHIP1−/−osteoclasts. These data establish a cell-intrinsic role for SHIP1 in osteoclasts, with inflammation as the key driver of the skeletal phenotype in SHIP1-deficient mice. Our findings demonstrate the central role of the immune system in steering physiological skeletal development.

Funder

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Jubiläumsstiftung von Swiss Life

Bern University Research Foundation

Lungenliga Schweiz

Lungenliga Bern

Robert Mathys Foundation

Publisher

Life Science Alliance, LLC

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