SHIP-deficient Mice Are Severely Osteoporotic Due to Increased Numbers of Hyper-resorptive Osteoclasts
Overview
Molecular Biology
Authors
Affiliations
The hematopoietic-restricted protein Src homology 2-containing inositol-5-phosphatase (SHIP) blunts phosphatidylinositol-3-kinase-initiated signaling by dephosphorylating its major substrate, phosphatidylinositol-3,4,5-trisphosphate. As SHIP(-/-) mice contain increased numbers of osteoclast precursors, that is, macrophages, we examined bones from these animals and found that osteoclast number is increased two-fold. This increased number is due to the prolonged life span of these cells and to hypersensitivity of precursors to macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-kappa B ligand (RANKL). Similar to pagetic osteoclasts, SHIP(-/-) osteoclasts are enlarged, containing upwards of 100 nuclei, and exhibit enhanced resorptive activity. Moreover, as in Paget disease, serum levels of interleukin-6 are markedly increased in SHIP(-/-) mice. Consistent with accelerated resorptive activity, 3D trabecular volume fraction, trabecular thickness, number and connectivity density of SHIP(-/-) long bones are reduced, resulting in a 22% loss of bone-mineral density and a 49% decrease in fracture energy. Thus, SHIP negatively regulates osteoclast formation and function and the absence of this enzyme results in severe osteoporosis.
Environmental and inflammatory factors influencing concurrent gut and lung inflammation.
Raftery A, Pattaroni C, Harris N, Tsantikos E, Hibbs M Inflamm Res. 2024; 73(12):2123-2139.
PMID: 39432107 PMC: 11632041. DOI: 10.1007/s00011-024-01953-x.
SHIP1 deficiency causes inflammation-dependent retardation in skeletal growth.
Safari F, Yeoh W, Perret-Gentil S, Klenke F, Dolder S, Hofstetter W Life Sci Alliance. 2024; 7(5).
PMID: 38388173 PMC: 10883774. DOI: 10.26508/lsa.202302297.
Chu E, Mychasiuk R, Green T, Zamani A, Dill L, Sharma R Front Neurosci. 2023; 17:1276495.
PMID: 37901420 PMC: 10603304. DOI: 10.3389/fnins.2023.1276495.
Regulation of Microglial Signaling by Lyn and SHIP-1 in the Steady-State Adult Mouse Brain.
Chu E, Mychasiuk R, Tsantikos E, Raftery A, LEstrange-Stranieri E, Dill L Cells. 2023; 12(19).
PMID: 37830592 PMC: 10571795. DOI: 10.3390/cells12192378.
Ginsenoside Rg2 inhibits osteoclastogenesis by downregulating the NFATc1, c-Fos, and MAPK pathways.
Lee S, Park S, Kim J, Kim N, Lee J BMB Rep. 2023; 56(10):551-556.
PMID: 37605614 PMC: 10618073.