title: Bone microenvironment specific roles of ITAM adapter signaling during bone remodeling induced by acute estrogen-deficiency.
abstract: Immunoreceptor tyrosine-based activation motif (ITAM) signaling mediated by DAP12 or Fcepsilon receptor Igamma chain (FcRgamma) have been shown to be critical for osteoclast differentiation and maturation under normal physiological conditions. Their function in pathological conditions is unknown. We studied the role of ITAM signaling during rapid bone remodeling induced by acute estrogen-deficiency in wild-type (WT), DAP12-deficient (DAP12-/-), FcRgamma-deficient (FcRgamma-/-) and double-deficient (DAP12-/-FcRgamma-/-) mice. Six weeks after ovariectomy (OVX), DAP12-/-FcRgamma-/- mice showed resistance to lumbar vertebral body (LVB) trabecular bone loss, while WT, DAP12-/- and FcRgamma-/- mice had significant LVB bone loss. In contrast, all ITAM adapter-deficient mice responded to OVX with bone loss in both femur and tibia of approximately 40%, relative to basal bone volumes. Only WT mice developed significant cortical bone loss after OVX. In vitro studies showed microenvironmental changes induced by OVX are indispensable for enhanced osteoclast formation and function. Cytokine changes, including TGFbeta and TNFalpha, were able to induce osteoclastogenesis independent of RANKL in BMMs from WT but not DAP12-/- and DAP12-/-FcRgamma-/- mice. FSH stimulated RANKL-induced osteoclast differentiation from BMMs in WT, but not DAP12-/- and DAP12-/-FcRgamma-/- mice. Our study demonstrates that although ITAM adapter signaling is critical for normal bone remodeling, estrogen-deficiency induces an ITAM adapter-independent bypass mechanism allowing for enhanced osteoclastogenesis and activation in specific bony microenvironments.
authors.affiliation: Department of Medicine, VA Medical Center, University of California San Francisco, San Francisco, California, United States of America; Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Yalei
authors.initials: Y
authors.lastname: Wu
authors.forename: James
authors.initials: J
authors.lastname: Torchia
authors.forename: Wei
authors.initials: W
authors.lastname: Yao
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Lane
authors.forename: Lewis L
authors.initials: LL
authors.lastname: Lanier
authors.forename: Mary C
authors.initials: MC
authors.lastname: Nakamura
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Humphrey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000502:physiology; D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000000981:diagnostic imaging; D004967:Estrogens / Q000172:deficiency*; D005260:Female; D007091:Image Processing, Computer-Assisted; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging; D051379:Mice; D018345:Mice, Knockout; D009929:Organ Size; D010010:Osteoclasts / Q000502:physiology; D010052:Ovariectomy; D011859:Radiography; D017452:Receptors, IgG / Q000172:deficiency / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014599:Uterus / Q000033:anatomy & histology / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004967:Estrogens; D017452:Receptors, IgG; C484963:Tyrobp protein, mouse