RT Journal Article
SR Electronic
T1 SHIP1 deficiency causes inflammation-dependent retardation in skeletal growth
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202302297
DO 10.26508/lsa.202302297
VO 7
IS 5
A1 Safari, Fatemeh
A1 Yeoh, Wen Jie
A1 Perret-Gentil, Saskia
A1 Klenke, Frank
A1 Dolder, Silvia
A1 Hofstetter, Willy
A1 Krebs, Philippe
YR 2024
UL https://www.life-science-alliance.org/content/7/5/e202302297.abstract
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.