PT  - JOURNAL ARTICLE
AU  - Safari, Fatemeh
AU  - Yeoh, Wen Jie
AU  - Perret-Gentil, Saskia
AU  - Klenke, Frank
AU  - Dolder, Silvia
AU  - Hofstetter, Willy
AU  - Krebs, Philippe
TI  - SHIP1 deficiency causes inflammation-dependent retardation in skeletal growth
AID  - 10.26508/lsa.202302297
DP  - 2024 May 01
TA  - Life Science Alliance
PG  - e202302297
VI  - 7
IP  - 5
4099  - https://www.life-science-alliance.org/content/7/5/e202302297.short
4100  - https://www.life-science-alliance.org/content/7/5/e202302297.full
SO  - Life Sci. Alliance2024 May 01; 7
AB  - 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 in Rag2−/−/Il2rg−/−/SHIP1−/− mice. Rag2−/−/Il2rg−/−/SHIP1−/− osteoclasts, however, displayed an intermediate transcriptomic signature between control and Rag2+/+/Il2rg+/+/SHIP1−/− osteoclasts while exhibiting aberrant in vitro development and functions similar to Rag2+/+/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.