Biomedical subjects

Deborah Veis Novack

Publications and source records attributed to Deborah Veis Novack.

6 recordsLinked to original sources

PubMed2007

Jawing about TNF: new hope for cherubism.

Mutations in the SH3-domain binding protein 2 (SH3BP2) are known to cause a rare childhood disorder called cherubism that is characterized by inflammation and bone loss in the jaw, but the mechanism has remained unclear. In this issue, Ueki et al. (Ueki et al., 2007) now demonstrate that a cherubism mutation activates mouse Sh3bp2 resulting in enhanced production of the cytokine TNF-alpha by myeloid cells, leading to both bone loss and inflammation.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Critical role of beta3 integrin in experimental postmenopausal osteoporosis.

UNLABELLED: We show that mice lacking beta3 integrin are protected from OVX-induced bone loss. Using a lentiviral-based strategy to express beta3 mutants in beta3(-/-) mice, we also show that beta3(S752), but not beta3(Y747/Y759), is important for osteoclastic bone resorption in vivo. INTRODUCTION: Mice lacking the beta3 integrin have dysfunctional osteoclasts and therefore accumulate bone mass with age. Thus, the alphavbeta3 integrin is a potential anti-osteoporosis target. Identifying components of the beta3 integrin that determine its function in vivo is essential for therapeutically exploiting the antiresorptive properties of alphavbeta3. MATERIALS AND METHODS: We used DXA and histomorphometry to assess bone loss after ovariectomy in wildtype and beta3 integrin null mice. We used lentiviral vectors carrying various human beta3 (hbeta3) integrin constructs to transduce beta3(-/-) bone marrow and reconstituted lethally irradiated beta3(-/-) mice with the transduced marrow. The expressed constructs include the intact integrin and two mutants, namely hbeta3(Y747F/Y759F) and hbeta3(S752P), each of which induces the bleeding dyscrasia, Glanzmann's thrombasthenia, in humans. Two months after transplantation, the expression of hbeta3 was measured by flow cytometry of marrow-derived macrophages. Osteoclast differentiation and function were assessed ex vivo by TRACP and actin-ring staining, respectively. Reconstituted mice were ovariectomized, and bone loss was assessed by DXA, histomorphometry, and serum TRACP5b assay. RESULTS: beta3(-/-) mice are protected from ovariectomy-induced bone loss, showing no difference in BMD compared with sham-operated controls. We successfully expressed hbeta3 integrins in beta3(-/-) hosts using lentiviral transduction of bone marrow. Two months after transplantation, 25-35% of marrow-derived macrophages expressed the hbeta3 constructs. Similar to its effect in vitro, hbeta3(WT) completely rescued the osteoclast and platelet phenotype of beta3(-/-) mice. Whereas platelet function remained deranged in beta3(-/-) mice overexpressing hbeta3(Y747F/Y759F), osteoclast function was fully restored. In contrast, beta3(-/-) mice expressing hbeta3(S752P) continued to exhibit prolonged bleeding times and dysfunctional osteoclasts in vitro and ex vivo. Most importantly, hbeta3(WT) and hbeta3(Y747F/Y759F) transplanted mice underwent equivalent ovariectomy-induced bone loss, whereas, like those bearing the control vector, hbeta3(S752P) transplanted mice were protected. CONCLUSIONS: Functional beta3 integrin is required for ovariectomy-induced bone loss. beta3(S752), but not beta3(Y747/Y759), is critical for osteoclast function in vivo.

Acid Phosphatase↗

PubMed2005

NF-(kappa)B-inducing kinase controls lymphocyte and osteoclast activities in inflammatory arthritis.

NF-(kappa)B is an important component of both autoimmunity and bone destruction in RA. NF-(kappa)B-inducing kinase (NIK) is a key mediator of the alternative arm of the NF-(kappa)B pathway, which is characterized by the nuclear translocation of RelB/p52 complexes. Mice lacking functional NIK have no peripheral lymph nodes, defective B and T cells, and impaired receptor activator of NF-kappaB ligand-stimulated osteoclastogenesis. We investigated the role of NIK in murine models of inflammatory arthritis using Nik-/- mice. The serum transfer arthritis model is initiated by preformed antibodies and required only intact neutrophil and complement systems in recipients. While Nik-/- mice had inflammation equivalent to that of Nik+/+ controls, they showed significantly less periarticular osteoclastogenesis and less bone erosion. In contrast, Nik-/- mice were completely resistant to antigen-induced arthritis (AIA), which requires intact antigen presentation and lymphocyte function but not lymph nodes. Additionally, transfer of Nik+/+ splenocytes or T cells to Rag2-/- mice conferred susceptibility to AIA, while transfer of Nik-/- cells did not. Nik-/- mice were also resistant to a genetic, spontaneous form of arthritis, generated in mice expressing both the KRN T cell receptor and H-2. Thus, NIK is important in the immune and bone-destructive components of inflammatory arthritis and represents a possible therapeutic target for these diseases.

Adoptive Transfer↗

PubMed2004

Marrow stromal cells and osteoclast precursors differentially contribute to TNF-alpha-induced osteoclastogenesis in vivo.

The marrow stromal cell is the principal source of the key osteoclastogenic cytokine receptor activator of NF-kappaB (RANK) ligand (RANKL). To individualize the role of marrow stromal cells in varying states of TNF-alpha-driven osteoclast formation in vivo, we generated chimeric mice in which wild-type (WT) marrow, immunodepleted of T cells and stromal cells, is transplanted into lethally irradiated mice deleted of both the p55 and p75 TNFR. As control, similarly treated WT marrow was transplanted into WT mice. Each group was administered increasing doses of TNF-alpha. Exposure to high-dose cytokine ex vivo induces exuberant osteoclastogenesis irrespective of in vivo TNF-alpha treatment or whether the recipient animals possess TNF-alpha-responsive stromal cells. In contrast, the osteoclastogenic capacity of marrow treated with lower-dose TNF-alpha requires priming by TNFR-bearing stromal cells in vivo. Importantly, the osteoclastogenic contribution of cytokine responsive stromal cells in vivo diminishes as the dose of TNF-alpha increases. In keeping with this conclusion, mice with severe inflammatory arthritis develop profound osteoclastogenesis and bone erosion independent of stromal cell expression of TNFR. The direct induction of osteoclast recruitment by TNF-alpha is characterized by enhanced RANK expression and sensitization of precursor cells to RANKL. Thus, osteolysis attending relatively modest elevations in ambient TNF-alpha depends upon responsive stromal cells. Alternatively, in states of severe periarticular inflammation, TNF-alpha may fully exert its bone erosive effects by directly promoting the differentiation of osteoclast precursors independent of cytokine-responsive stromal cells and T lymphocytes.

Animals↗

PubMed2003

TSH, the bone suppressing hormone.

The skeleton is a dynamic organ whose structural integrity depends on constant remodeling, controlled by many local and systemic factors. In this issue of Cell, identify thyroid-stimulating hormone (TSH) as an important regulator of this process.

Animals↗

PubMed2003

The IkappaB function of NF-kappaB2 p100 controls stimulated osteoclastogenesis.

The prototranscription factor p100 represents an intersection of the NF-kappaB and IkappaB families, potentially serving as both the precursor for the active NF-kappaB subunit p52 and as an IkappaB capable of retaining NF-kappaB in the cytoplasm. NF-kappaB-inducing kinase (NIK) controls processing of p100 to generate p52, and thus NIK-deficient mice can be used to examine the biological effects of a failure in such processing. We demonstrate that treatment of wild-type osteoclast precursors with the osteoclastogenic cytokine receptor activator of NF-kappaB ligand (RANKL) increases both expression of p100 and its conversion to p52, resulting in unchanged net levels of p100. In the absence of NIK, p100 expression is increased by RANKL, but its conversion to p52 is blocked, leading to cytosolic accumulation of p100, which, acting as an IkappaB protein, binds NF-kappaB complexes and prevents their nuclear translocation. High levels of unprocessed p100 in osteoclast precursors from NIK-/- mice or a nonprocessable form of the protein in wild-type cells impair RANKL-mediated osteoclastogenesis. Conversely, p100-deficient osteoclast precursors show enhanced sensitivity to RANKL. These data demonstrate a novel, biologically relevant means of regulating NF-kappaB signaling, with upstream control and kinetics distinct from the classical IkappaBalpha pathway.

Animals↗