SHIP-deficient mice are severely osteoporotic due to increased numbers of hyper-resorptive osteoclasts

Abstract

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.

SHIP1 Regulates MSC Numbers and Their Osteolineage Commitment by Limiting Induction of the PI3K/Akt/β-Catenin/Id2 Axis

“…We confirm the earlier findings of Takeshita et al [23] and Peng et al [24] that showed a cell autonomous role for SHIP in limiting the response of OC to M-CSF and RANKL ex vivo. However, our findings also demonstrate a novel role for SHIP1 in osteogenesis and indicate a SHIP-competent OB compartment regulates OC differentiation and resorptive capacity in vivo and can prevent SHIP1-deficient OCs from undergoing dysregulated differentiation and function in situ.…”

“…TRAP staining of bone sections indicated there were normal numbers of OC present in the bone of LysMCre-SHIP flox/flox as compared to SHIP flox/flox mice (Fig. 6G), but, and consistent with previous findings, [23,24] SHIP-deficient OC from LysMCreSHIP flox/flox expand to a greater extent when cultured ex vivo in the presence of M-CSF and receptor activator of nuclear factor kappa-B ligand (RANKL) relative to OC from SHIP flox/flox controls (Fig. 6H, I).…”

“…A previous study suggested that germline SHIP1 -/ -mice were osteoporotic due to increased numbers of OC in vivo that were shown to be hyper-resorptive ex vivo [23]. Our collaborative study confirmed the hyper-resorptive capacity of SHIP1 -/ -OC ex vivo and attributed this to a failure of SHIP1 to block PI3K recruitment to DAP12: TREM2 complexes expressed by OC [24].…”

“…In addition, BM-derived SHIP1 -/ -OBs have less alkaline phosphatase (ALP) activity required for bone formation indicating impaired OB development and function [22]. SHIP -/ -mutant mice have previously been reported to be osteoporotic [23]. This pathology was attributed to hyperresorptive activity by myeloid-derived OCs [23] resulting from unopposed PI3K signaling at DAP12-associated receptors [24].…”

“…SHIP -/ -mutant mice have previously been reported to be osteoporotic [23]. This pathology was attributed to hyperresorptive activity by myeloid-derived OCs [23] resulting from unopposed PI3K signaling at DAP12-associated receptors [24].…”