SHIP1 Negatively Regulates Proliferation of Osteoclast Precursors via Akt-Dependent Alterations in D-Type Cyclins and p27

Abstract

Osteoclasts arise from macrophage progenitors in bone marrow (BMMs) as a consequence of signaling events elicited by M-CSF and receptor activator of NF-κB ligand, acting on their unique receptors, via c-Fms and receptor activator of NF-κB. Both receptors activate the PI3K and MAPK pathways, which promote cell proliferation and survival. SHIP1 is essential for normal bone homeostasis, as mice lacking the protein exhibit osteoporosis resulting from increased numbers of hyper-resorptive osteoclasts. In this study, we show that BMMs from SHIP1 null mice respond to M-CSF, but not receptor activator of NF-κB ligand, by increasing Akt activation. In consequence, there are up-regulation of D-type cyclins, down-regulation of the cyclin-dependent kinase inhibitor p27, and, therefore, increased phosphorylation of the retinoblastoma protein and cell proliferation. Surprisingly, cell survival of wild-type and knockout BMMs is unaltered. Finally, osteoclastogenesis and periarticular bone erosions are markedly increased in SHIP1−/− mice with inflammatory arthritis, a condition characterized by increased M-CSF expression. The SHIP1/Akt pathway therefore suppresses bone loss in pathological states associated with an excess of the cytokine.

Activin A inhibits RANKL-mediated osteoclast formation, movement and function in murine bone marrow macrophage cultures

“…As others have shown, transduced cells plated on bone were delayed in their differentiation, requiring ,8 days to become mature TRAP+ multinucleated cells (MNCs) (Zhou et al, 2006). As expected, RANKL treatment significantly increased motility throughout the time course of OCL maturation (Fig.…”

“…Viral transduction and time-lapse video imaging of pre-osteoclasts and osteoclasts on bone slices Expanded populations of adherent mBMMs were transduced on day 3 in 10-cm Petri dishes with GFP-actin as previously described (Zhou et al, 2006). Plat-E packaging cells were transiently transfected by calcium phosphate precipitation.…”

PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk

“…Both strains display splenomegaly with extramedullary hematopoiesis and an increased number and proliferation of myeloid progenitor cells (3,34,53). In addition, they also share a phenotype of increased osteoclastogenesis and osteoclast activity, resulting in osteopenia and osteoporosis (32,56). These features shared between SHIP1 2/2 and CMO mice suggest that they are components of a common signaling pathway.…”

Cdc42 regulates bone modeling and remodeling in mice by modulating RANKL/M-CSF signaling and osteoclast polarization

“…We previously established that M-CSF promotes proliferation of primary macrophages by activating D-type cyclins and their downstream effector, hyperphosphorylated Rb (21). Thus, we measured these cell cycling molecules in the context of Cdc42 loss and gain of function.…”