Safari, Fatemeh; Yeoh, Jeremy; Siegrist, Mark; Dolder, Silvia; Strunz, Franziska; Hofstetter, Willy; Krebs, Philippe (May 2022). Inositol Phosphatase SHIP1 – a Regulator of Osteoclast Lineage Cell Development and Activity. Bone reports, 16, p. 101404. Elsevier 10.1016/j.bonr.2022.101404
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Introduction: Src-homology (SH) 2 domain-containing inositol-5-phosphatase 1 (SHIP1) is a negative regulator of the PI3K/Akt pathway that is expressed in hematopoietic cells. Osteoclast (OC) development depends on two essential pathways activated by receptor activator of NF-κB ligand (RANKL) and colony-stimulating factor-1 (CSF-1). Both pathways involve PI3K in their signalling and may therefore be regulated by SHIP1. SHIP1-deficient mice ((SHIPstyx/styx) are characterized by low bone density that has been suggested to be caused by an increased number of hyperactive OC.
Purpose: This study aimed to investigate cellular mechanisms leading to low bone mass in SHIP1-deficient mice.
Methods: MicroCT analysis of vertebrae and femora was performed to evaluate bone structure in vivo. To study OC development in vitro, progenitor cells (OPC) from SHIP1-deficient SHIPstyx/styx and control mice were cultured with RANKL and CSF-1. Osteoclastogenesis was assessed using an XTT cell viability assay and by determining TRAP activity. Furthermore, the capacity of OC to dissolve amorphous calcium phosphate (CaP) was determined.
Results: In vivo, BV/TV of vertebrae and femora of SHIPstyx/styx mice was decreased compared to wt animals (40% and 35%, respectively, p<0.01). Trabecular number in vertebrae from SHIPstyx/styx mice was increased by 26%, while thickness was decreased by 30% (p<0.01). In femora from SHIPstyx/styx, trabecular thickness was reduced by 25% (p<0.05), whereas trabecular number remained unchanged. In vitro, SHIPstyx/styx OPC showed a 1.5-fold increased proliferation compared to controls (p<0.001), yet the number of OPC-derived OC was reduced by 40%. The capacity of SHIPstyx/styx OC to dissolve CaP was decreased by 60% compared to controls (p<0.001).
Conclusions: Our data indicates a central role for SHIP1 in OC development and activity in vitro. The low bone mass phenotype in SHIPstyx/styx mice, however, may be caused by reduced bone formation or by the wasting disease and systemic inflammatory condition characteristic of SHIP1-deficient mice.
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