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ABSTRACT: Ubiquitin E3 ligase-mediated protein degradation promotes proteasomal degradation of key positive regulators of osteoblast functions. For example, the E3 ligases, Smurf1, Itch and Wwp1, promote degradation of Runx2, JunB, and CXCR4 proteins to inhibit their functions. However, the role of E3 ligases in age-associated bone loss is unknown. We found that the expression level of Wwp1, but not Smurf1 or Itch, was significantly increased in CD45(-) bone marrow-derived mesenchymal stem cells (MSCs) from 6- and 12-month-old WT mice. Wwp1(-/-) mice developed increased bone mass as they aged, associated with increased bone formation rates and normal bone resorption parameters. Bone marrow stromal cells (BMSCs) from Wwp1(-/-) mice formed increased numbers and areas of alkaline phosphatase(+) and Alizarin Red(+) nodules and had increased migration potential towards CXCL12 gradients. Runx2, JunB and CXCR4 protein levels were significantly increased in Wwp1(-/-) BMSCs. Wwp1(-/-) BMSCs had increased amount of ubiquitinated JunB protein, but Runx2 ubiquitination was no change. Knocking-down JunB in Wwp1(-/-) BMSCs returned Runx2 protein levels to that in WT cells. Thus, Wwp1 negatively regulates osteoblast functions by affecting both their migration and differentiation. Mechanisms designed to decrease Wwp1 levels in BMSCs may represent a new approach to prevent the decrease in osteoblastic bone formation associated with aging. © 2013 American Society for Bone and Mineral Research.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2013; · 6.04 Impact Factor
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ABSTRACT: Osteoclasts are the bone resorbing cells essential for bone remodeling. Osteoclasts are formed from hematopoietic progenitors in the monocyte/macrophage lineage. Osteoclastogenesis is composed of several steps including progenitor survival, differentiation to mono-nuclear pre-osteoclasts, fusion to multi-nuclear mature osteoclasts, and activation to bone resorbing osteoclasts. The regulation of osteoclastogenesis has been extensively studied, in which the receptor activator of NF-κB ligand (RANKL)-mediated signaling pathway and downstream transcription factors play essential roles. However, less is known about osteoclast fusion, which is a property of mature osteoclasts and is required for osteoclasts to resorb bone. Several proteins that affect cell fusion have been identified. Among them, dendritic cell-specific transmembrane protein (DC-STAMP) is directly associated to osteoclast fusion in vivo. Cytokines and factors influence osteoclast fusion through regulation of DC-STAMP. Here we review the recently discovered new factors that regulate osteoclast fusion with specific focus on DC-STAMP. A better understanding of the mechanistic basis of osteoclast fusion will lead to the development of a new therapeutic strategy for bone disorders due to elevated osteoclast bone resorption. Cell-cell fusion is essential for a variety of cellular biological processes. In mammals, there is a limited number of cell types that fuse to form multinucleated cells, such as the fusion of myoblasts for the formation of skeletal muscle and the fusion of cells of the monocyte/macrophage lineage for the formation of multinucleated osteoclasts and giant cells. In most cases, cell-cell fusion is beneficial for cells by enhancing function. Myoblast fusion increases myofiber size and diameter and thereby increases contractile strength. Multinucleated osteoclasts have far more bone resorbing activity than their mono-nuclear counterparts. Multinucleated giant cells are much more efficient in the removal of implanted materials and bacteria due to chronic infection than macrophages. Therefore, they are also called foreign-body giant cells. Cell fusion is a complicated process involving cell migration, chemotaxis, cell-cell recognition and attachment, as well as changes into a fusion-competent status. All of these steps are regulated by multiple factors. In this review, we will discuss osteoclast fusion and regulation.
World journal of orthopedics. 12/2012; 3(12):212-22.
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ABSTRACT: OBJECTIVE.: Glucocorticoid (GC) therapy is associated with increased fracture risk in rheumatoid arthritis (RA) patients. To elucidate the cause of this increased risk, we examined the effects of chronic inflammatory-erosive arthritis and GC treatment on bone quality, structure, and biomechanical properties in a murine model. METHODS.: Transgenic mice expressing human TNF-α-transgene (TNF-tg) with established arthritis and wild-type (WT) littermates were continually treated with GC (subcutaneous prednisolone controlled-release pellet; 5 mg/kg/day) or placebo for 14, 28 and 42 days. Microstructure, biomechanical properties, chemical composition, and morphology of tibiae and lumbar vertebral bodies were assessed by micro-CT, biomechanical testing, Raman spectroscopy, and histology, respectively. Serum markers of bone turnover were also determined. RESULTS.: TNF-tg and GC treatment additively decreased mechanical strength and stiffness in both tibiae and vertebral bodies. GC treatment in the TNF-tg mice increased the ductility of tibiae under torsional loading. These changes were associated with significant alterations in the biochemical and structural composition of the mineral and organic components of the bone matrix, a decrease in osteoblast activity and bone formation, and an increase in osteoclastic activity. CONCLUSIONS.: Our findings indicate that the concomitant decrease in bone strength and increase in ductility associated with chronic inflammation and GC therapy, coupled with the significant changes in the bone quality and structure, may increase the susceptibility of the bone to failure under low energy loading. This may explain the mechanism of symptomatic insufficiency fractures in patients with RA receiving GC therapy without radiographic manifestation of fracture.
Arthritis & Rheumatism 07/2012; · 7.87 Impact Factor
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Arthritis & Rheumatism 02/2012; 64(6):2048-50. · 7.87 Impact Factor
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ABSTRACT: RelB and nuclear factor κB (NF-κB2) are the main effectors of NF-κB noncanonical signaling and play critical roles in many physiological processes. However, their role in hematopoietic stem/progenitor cell (HSPC) maintenance has not been characterized. To investigate this, we generated RelB/NF-κB2 double-knockout (dKO) mice and found that dKO HSPCs have profoundly impaired engraftment and self-renewal activity after transplantation into wild-type recipients. Transplantation of wild-type bone marrow cells into dKO mice to assess the role of the dKO microenvironment showed that wild-type HSPCs cycled more rapidly, were more abundant, and had developmental aberrancies: increased myeloid and decreased lymphoid lineages, similar to dKO HSPCs. Notably, when these wild-type cells were returned to normal hosts, these phenotypic changes were reversed, indicating a potent but transient phenotype conferred by the dKO microenvironment. However, dKO bone marrow stromal cell numbers were reduced, and bone-lining niche cells supported less HSPC expansion than controls. Furthermore, increased dKO HSPC proliferation was associated with impaired expression of niche adhesion molecules by bone-lining cells and increased inflammatory cytokine expression by bone marrow cells. Thus, RelB/NF-κB2 signaling positively and intrinsically regulates HSPC self-renewal and maintains stromal/osteoblastic niches and negatively and extrinsically regulates HSPC expansion and lineage commitment through the marrow microenvironment.
Stem Cells 01/2012; 30(4):709-18. · 7.78 Impact Factor
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Kristina Subik,
Lei Shu,
Chengyu Wu,
Qianqian Liang,
David Hicks,
Brendan Boyce,
Linda Schiffhauer,
Di Chen,
Ceshi Chen,
Ping Tang, Lianping Xing
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ABSTRACT: Advanced breast cancers preferentially metastasize to bone where cells in the bone microenvironment produce factors that enhance breast cancer cell homing and growth. Expression of the ubiquitin E3 ligase WWP1 is increased in some breast cancers, but its role in bone metastasis has not been investigated. Here, we studied the effects of WWP1 and itch, its closest family member, on breast cancer bone metastasis. First, we immunostained a multi-tumor tissue microarray and a breast cancer tissue microarray and demonstrated that WWP1 and ITCH are expressed in some of breast cancer cases. We then knocked down WWP1 or itch in MDA-MB-231 breast cancer cells using shRNA and inoculated these cells and control cells into the left ventricle of athymic nude mice. Radiographs showed that mice given shWWP1 cells had more osteolytic lesions than mice given control MDA-MB-231 cells. Histologic analysis confirmed osteolysis and showed significantly increased tumor area in bone marrow of the mice. WWP1 knockdown did not affect cell growth, survival or osteoclastogenic potential, but markedly increased cell migration toward a CXCL12 gradient in vitro. Furthermore, WWP1 knockdown significantly reduced CXCL12-induced CXCR4 lysosomal trafficking and degradation. In contrast, itch knockdown had no effect on MDA-MB-231 cell bone metastasis. Taken together, these findings demonstrate that WWP1 negatively regulates cell migration to CXCL12 by limiting CXCR4 degradation to promote breast cancer metastasis to bone and highlight the potential utility of WWP1 as a prognostic indicator for breast cancer bone metastasis.
Bone 01/2012; 50(4):813-23. · 4.02 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints; the etiology of RA is largely unknown. Recent studies in mice demonstrated that alterations in lymphatics from affected joints precede flares. Thus, we aimed to develop novel methods for measuring lymph node pressure and lymph viscosity in limbs of mice. Pressure measurements were performed by inserting a glass micropipette connected to a pressure transducer into popliteal lymph nodes (PLN) or axillary lymph nodes (ALN) of mice; subsequently, we determined that the lymphatic pressures of water were 9 and 12 cm, respectively. We are also developing methods for measuring lymph viscosity in lymphatic vessels afferent to PLN, which can be measured by multiphoton fluorescence recovery after photobleaching (MP-FRAP) of fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA) injected into the hind footpad. These results demonstrate the potential of lymph node pressure and lymph viscosity measurements, and future studies to test these outcomes as biomarkers of arthritic flare are warranted.
Annals of the New York Academy of Sciences 12/2011; 1240:47-52. · 3.15 Impact Factor
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ABSTRACT: Src is a nonreceptor tyrosine kinase essential for the activation of osteoclasts, the cells that degrade bone. Src also regulates normal cell functions, cancer cell growth and metastasis to organs, including bone where tumor cells induce bone destruction by osteoclasts. Src inhibitors prevent bone destruction and tumor cell growth in animal models of metastatic bone disease, and some are being investigated in clinical trials, particularly in patients with prostate cancer, which has high bone metastatic potential. Here, we review how Src regulates osteoclast formation, activation and survival and the results of preclinical and clinical trials of Src inhibitors, which show some promise in inhibiting the effects of tumor cells on the skeleton.
Clinical investigation. 12/2011; 1(12):1695-1706.
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ABSTRACT: Pancytopenia is a major cause of morbidity in acute myeloid leukemia (AML), yet its cause is unclear. Normal osteoblastic cells have been shown to support hematopoiesis. To define the effects of leukemia on osteoblastic cells, we used an immunocompetent murine model of AML. Leukemic mice had inhibition of osteoblastic cells, with decreased serum levels of the bone formation marker osteocalcin. Osteoprogenitor cells and endosteal-lining osteopontin(+) cells were reduced, and osteocalcin mRNA in CD45(-) marrow cells was diminished. This resulted in severe loss of mineralized bone. Osteoclasts were only transiently increased without significant increases in bone resorption, and their inhibition only partially rescued leukemia-induced bone loss. In vitro data suggested that a leukemia-derived secreted factor inhibited osteoblastic cells. Because the chemokine CCL-3 was recently reported to inhibit osteoblastic function in myeloma, we tested its expression in our model and in AML patients. Consistent with its potential novel role in leukemic-dependent bone loss, CCL-3 mRNA was significantly increased in malignant marrow cells from leukemic mice and from samples from AML patients. Based on these results, we propose that therapeutic mitigation of leukemia-induced uncoupling of osteoblastic and osteoclastic cells may represent a novel approach to promote normal hematopoiesis in patients with myeloid neoplasms.
Blood 09/2011; 119(2):540-50. · 9.90 Impact Factor
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ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease with episodic flares in affected joints. However, how arthritic flare occurs only in select joints during a systemic autoimmune disease remains an enigma. To better understand these observations, we developed longitudinal imaging outcomes of synovitis and lymphatic flow in mouse models of RA, and identified that asymmetric knee flare is associated with ipsilateral popliteal lymph node (PLN) collapse and the translocation of CD23(+)/CD21(hi) B-cells (B-in) into the paracortical sinus space of the node. In order to understand the relationship between this B-in translocation and lymph drainage from flaring joints, we tested the hypothesis that asymmetric tumor necrosis factor (TNF)-induced knee arthritis is associated with ipsilateral PLN and iliac lymph node (ILN) collapse, B-in translocation, and decreased afferent lymphatic flow.
TNF transgenic (Tg) mice with asymmetric knee arthritis were identified by contrast-enhanced (CE) magnetic resonance imaging (MRI), and PLN were phenotyped as "expanding" or "collapsed" using LNcap threshold = 30 (Arbitrary Unit (AU)). Inflammatory-erosive arthritis was confirmed by histology. Afferent lymphatic flow to PLN and ILN was quantified by near infrared imaging of injected indocyanine green (NIR-ICG). The B-in population in PLN and ILN was assessed by immunohistochemistry (IHC) and flow cytometry. Linear regression analyses of ipsilateral knee synovial volume and afferent lymphatic flow to PLN and ILN were performed.
Afferent lymph flow to collapsed nodes was significantly lower (P < 0.05) than flow to expanding nodes by NIR-ICG imaging, and this occurred ipsilaterally. While both collapsed and expanding PLN and ILN had a significant increase (P < 0.05) of B-in compared to wild type (WT) and pre-arthritic TNF-Tg nodes, B-in of expanding lymph nodes (LN) resided in follicular areas while B-in of collapsed LN were present within LYVE-1+ lymphatic vessels. A significant correlation (P < 0.002) was noted in afferent lymphatic flow between ipsilateral PLN and ILN during knee synovitis.
Asymmetric knee arthritis in TNF-Tg mice occurs simultaneously with ipsilateral PLN and ILN collapse. This is likely due to translocation of the expanded B-in population to the lumen of the lymphatic vessels, resulting in a dramatic decrease in afferent lymphatic flow. PLN collapse phenotype can serve as a new biomarker of knee flare.
Arthritis research & therapy 08/2011; 13(4):R138. · 4.27 Impact Factor
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ABSTRACT: Patients with chronic inflammatory disorders, such as rheumatoid arthritis, often have osteoporosis due to a combination of Tumor necrosis factor-induced increased bone resorption and reduced bone formation. To test if TNF inhibits bone formation by affecting the commitment and differentiation of mesenchymal stem cells (MSCs) into osteoblasts, we examined the osteogenic potential of MSCs from TNF transgenic (TNF-Tg) mice, a model of chronic inflammatory arthritis. MSC-enriched cells were isolated from bone marrow stromal cells using negative selection with anti-CD45 antibody coated magnetic beads. The expression profile of MSC surface markers the osteogenic, chondrogenic, and adipogenic properties of CD45(-) cells were confirmed by FACS and cell differentiation assays. MSC-enriched CD45(-) cells from TNF-Tg mice formed significantly decreased numbers of fibroblast and ALP(+) colonies and had a decreased expression of osteoblast marker genes. As TNF may upregulate ubiquitin ligases, which negatively regulate osteoblast differentiation, we examined the expression levels of several ubiquitin ligases and found that Wwp1 expression was significantly increased in MSC-enriched CD45(-) cells of TNF-Tg mice. Wwp1 knockdown rescued impaired osteoblast differentiation of TNF-Tg CD45(-) cells. Wwp1 promotes ubiquitination and degradation of JunB, an AP-1 transcription factor that positively regulates osteoblast differentiation. Injection of TNF into wild-type mice resulted in decreased osteoblast differentiation of MSCs and increased JunB ubiquitination, which was completely blocked in Wwp1(-/-) mice. Thus, Wwp1 targets JunB for ubiquitination and degradation in MSCs after chronic exposure to TNF, and inhibition of Wwp1 in MSCs could be a new mechanism to limit inflammation-mediated osteoporosis by promoting their differentiation into osteoblasts.
Stem Cells 08/2011; 29(10):1601-10. · 7.78 Impact Factor
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ABSTRACT: To investigate whether the enhancement of joint lymphangiogenesis by injection of vascular endothelial growth factor C (VEGF-C) adeno-associated virus (AAV) into the affected joints has therapeutic efficacy in chronic inflammatory arthritis in mice.
Tumor necrosis factor-transgenic (TNF-Tg) mice were used as a model of chronic inflammatory arthritis. Human VEGF-C was cloned into an AAV expression vector to generate AAV-VEGF-C. The joints of TNF-Tg mice were injected with AAV-VEGF-C or AAV-luciferase (AAV-Luc) as a control. During the 4 months following injection, magnetic resonance imaging of the joints and lymphatic imaging were performed to assess changes in synovial volume and lymph flow from the joint tissues to local draining lymph nodes. Joint inflammation, bone erosion, and cartilage loss were examined by histologic analyses. Lymphatic vessel formation was assessed using immunohistochemistry.
Intraarticular administration of AAV-VEGF-C virus significantly attenuated the increase in synovial volume and increased lymphatic vessel number in the joint sections, as compared with that in control AAV-Luc-injected joints, during the 4-month period. This was accompanied by a reduction in the area of inflammation, bone erosion, cartilage loss, and osteoclast numbers. Lymph flow from the joints to local draining lymph nodes was slower in TNF-Tg mice than in wild-type littermates, and was significantly improved with AAV-VEGF-C treatment.
Intraarticular injection of AAV-VEGF-C increased lymphangiogenesis and improved lymphatic drainage from the inflamed joints of mice, resulting in attenuation of joint tissue damage. Thus, improvement of joint lymphatic function by local administration of lymphatic growth factors represents a new therapeutic approach for chronic inflammatory arthritis.
Arthritis & Rheumatism 05/2011; 63(8):2318-28. · 7.87 Impact Factor
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Qian-Qian Liang,
Xiao-Feng Li,
Quan Zhou, Lianping Xing,
Shao-Dan Cheng,
Dao-Fang Ding,
Le-Qin Xu,
De-Zhi Tang,
Qin Bian,
Zhi-Jie Xi,
Chongjian Zhou,
Qi Shi,
Yong-Jun Wang
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ABSTRACT: Human chondrocytes and annulus fibrosus cells of intervertebral disc (IVD) express osteoprotegerin (OPG), but the effect of OPG on the pathogenesis of IVD degeneration remains unknown. Here we assessed the phenotype change of IVD in OPG(-/-) mice.
The IVDs from 12-, 20-, and 28-week-old OPG(-/-) mice and WT controls were subjected to histologic analyses including TRAP staining for osteoclasts, immunostaining for OPG and type I collagen protein expression, and TUNEL staining for apoptosis. The IVD tissues were also subjected to real time RT-PCR for mRNA expression of genes for osteoblast-osterix, ALP, and osteocalcin; for osteoclasts-trap, rank, mmp9 and cathepsin K, and for chondrocytes-aggrecan, mmp13 and Col10.
OPG protein expresses at the cells of endplate cartilage and annulus fibrosis in IVDs of WT mice. Compared to WT mice, OPG(-/-) mice developed aging related cartilage loss and bony tissue appearance at the endplate. Stating from 20 weeks of age, IVDs from OPG(-/-) mice expressed significantly increased mmp13 and Col10 levels, which is associated with increased osteoblast number and elevated expression of osteoblast marker genes. Furthermore, TRAP+ osteoclasts were presented in the endplate cartilage of OPG(-/-) mice. These osteoclasts localized adjacently to and erosion into the cartilage. Increased expression of RANK, mmp9 and cathepsin k was detected in OPG(-/-) IVDs.
OPG at IVD plays an important role for maintaining the integrity of endplate cartilage during aging by preventing endplate cartilage from osteoclast-mediated resorption.
Bone 04/2011; 48(6):1362-9. · 4.02 Impact Factor
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ABSTRACT: The homologous to the E6-associated protein carboxyl terminus (HECT) domain E3 ubiquitin ligase Smurf1 is the first E3 ligase to be implicated in regulating bone cell function. The involvement of Smurf1 in multiple signaling pathways and pathological conditions is presently an area of extensive scientific interest. This review highlights recent works exploring Smurf-regulated biological processes in bone cells and highlights recent discoveries surrounding the regulatory mechanisms modulating its catalytic activity and substrate recognition capability. Moreover, we discuss the relevance of targeting the HECT E3s through the development of small-molecule inhibitors as an anticancer therapeutic strategy.
Journal of Cellular Biochemistry 06/2010; 110(3):554-63. · 2.87 Impact Factor
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ABSTRACT: Anti-CD20 B cell depletion therapy (BCDT) is very effective for some patients with rheumatoid arthritis (RA); however the pathogenic role of B lymphocytes in RA and the primary targets of BCDT are unknown. The human TNF transgenic (hTNF-Tg) mouse model of RA displays a chronic, progressive disease that spreads from distal to proximal joints and is generally considered to be adaptive immune system independent. We have previously reported that knee arthritis in hTNF-Tg mice is accompanied by structural and functional changes of the adjoining popliteal lymph node (PLN), detectable by contrast-enhanced magnetic resonance imaging. To better understand these changes, in this paper we show that onset of knee synovitis and focal erosions are paralleled by PLN contraction and accumulation of large numbers of B cells in the lymphatic sinus spaces within the node. Flow cytometry from TNF-Tg mice 2, 4-5, and 8-12 mo old demonstrated that B cell accumulation in the PLN follows ankle arthritis, but commences before knee disease, and involves early expansion of CD21(hi), CD23(+), IgM(hi), CD1d(+), activation marker-negative, polyclonal B cells that are found to be specifically restricted to lymph nodes draining inflamed, arthritic joints. The same B cell population also accumulates in PLNs of K/BxN mice with autoantigen-dependent arthritis. Strikingly, we show that BCDT ameliorates hTNF-Tg disease and clears follicular and CD21(hi), CD23(+) B cells from the PLNs. On the basis of these findings, we propose a model whereby B cells contribute to arthritis in mice, and possibly RA, by directly affecting the structure, composition, and function of joint-draining lymph nodes.
The Journal of Immunology 06/2010; 184(11):6142-50. · 5.79 Impact Factor
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Dan Li,
Kirill Gromov,
Steven T. Proulx,
Chao Xie,
Jie Li,
Daniel P. Crane,
Kjeld Søballe,
Regis J. O’Keefe,
Hani A. Awad, Lianping Xing,
Edward M. Schwarz
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ABSTRACT: The effects of antiresorptive agents (e.g., alendronate [Aln], osteoprotegerin [OPG]) on bone infection are unknown. Thus, their effects on implant-associated osteomyelitis (OM) were investigated in mice using PBS (placebo), gentamycin, and etanercept (TNFR:Fc) controls. None of the drugs affected humoral immunity, angiogenesis, or chronic infection. However, the significant (P < 0.05 vs. PBS) inhibition of cortical osteolysis and decreased draining lymph node size in Aln- and OPG-treated mice was associated with a significant (P < 0.05) increase in the incidence of high-grade infections during the establishment of OM. In contrast, the high-grade infections in TNFR:Fc-treated mice were associated with immunosuppression, as evidenced by the absence of granulomas and presence of Gram+ biofilm in the bone marrow. Collectively, these findings indicate that although antiresorptive agents do not exacerbate chronic OM, they can increase the bacterial load during early infection by decreasing lymphatic drainage and preventing the removal of necrotic bone that harbors the bacteria.
Annals of the New York Academy of Sciences 04/2010; 1192(1):84 - 94. · 3.15 Impact Factor
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ABSTRACT: The rapid evolution of reliable technology combined with increasing number of specific markers for lymphatic endothelial cells (LECs) facilitates the investigation of lymphangiogenesis in developing and diseased tissues. Here, we injected incomplete Freund's adjuvant (IFA) peritoneally into BALB/c and nonobese diabetic (NOD) mice to induce lymphangioma and found atypical lymphatic accumulations with intervening fibrous tissue and lymphoid aggregates. Lymphatic markers, LYVE-1 and podoplanin, were used to specifically define the morphological features of the neoplastic lymphatics. The NOD mice (affected by an autoimmune disorder) had fewer and smaller lymphangiomas than the BALB/c mice. Injection of IFA in the footpad skin of the mice also disturbed draining regional lymph node lymphangiogenesis and caused enlargement of popliteal lymph nodes. Molecular analyses of the LECs indicated potential interventions for lymphangioma through vascular endothelial growth factor (VEGF)-A/-C/-D and their receptors, VEGF receptors-2/-3, and Prox-1 signaling pathways. These findings represent an important link between multiple factors and lymphatic disorders.
Microvascular Research 04/2010; 80(2):195-201. · 2.83 Impact Factor
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ABSTRACT: In contrast to rheumatoid arthritis (RA), the joint inflammation referred to as Jaccoud's arthritis that occurs in systemic lupus erythematosus (SLE) is nonerosive. Although the mechanism responsible is unknown, the antiosteoclastogenic cytokine interferon-alpha (IFNalpha), whose transcriptome is present in SLE monocytes, may be responsible. This study was undertaken to examine the effects of IFNalpha and lupus on osteoclasts and erosion in the (NZB x NZW)F(1) mouse model of SLE with K/BxN serum-induced arthritis.
Systemic IFNalpha levels in (NZB x NZW)F(1) mice were elevated by administration of AdIFNalpha. SLE disease was marked by anti-double-stranded DNA (anti-dsDNA) antibody titer and proteinuria, and Ifi202 and Mx1 expression represented the IFNalpha transcriptome. Microfocal computed tomography was used to evaluate bone erosions. Flow cytometry for CD11b and CD11c was used to evaluate the frequency of circulating osteoclast precursors (OCPs) and myeloid dendritic cells (DCs) in blood.
Administration of AdIFNalpha to (NZB x NZW)F(1) mice induced osteopetrosis. (NZB x NZW)F(1) mice without autoimmune disease were fully susceptible to focal erosions in the setting of serum-induced arthritis. However, (NZB x NZW)F(1) mice with high anti-dsDNA antibody titers and the IFNalpha transcriptome were protected against bone erosions. AdIFNalpha pretreatment of NZW mice before K/BxN serum administration also resulted in protection against bone erosion (r(2) = 0.4720, P < 0.01), which was associated with a decrease in the frequency of circulating CD11b+CD11c- OCPs and a concomitant increase in the percentage of CD11b+CD11c+ cells (r(2) = 0.6330, P < 0.05), which are phenotypic of myeloid DCs.
These findings suggest that IFNalpha in SLE shifts monocyte development toward myeloid DCs at the expense of osteoclastogenesis, thereby resulting in decreased bone erosion.
Arthritis & Rheumatism 04/2010; 62(4):1127-37. · 7.87 Impact Factor
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ABSTRACT: To develop an in vivo imaging method to assess lymphatic draining function in the K/BxN mouse model of inflammatory arthritis.
Indocyanine green, a near-infrared fluorescent dye, was injected intradermally into the footpads of wild-type mice, mouse limbs were illuminated with an 806-nm near-infrared laser, and the movement of indocyanine green from the injection site to the draining popliteal lymph node (LN) was recorded with a CCD camera. Indocyanine green near-infrared images were analyzed to obtain 5 measures of lymphatic function across time. Images of K/BxN arthritic mice and control nonarthritic littermates were obtained at 1 month of age, when acute joint inflammation commenced, and again at 3 months of age, when joint inflammation became chronic. Lymphangiogenesis in popliteal LNs was assessed by immunochemistry.
Indocyanine green and its transport within lymphatic vessels were readily visualized, and quantitative measures were derived. During the acute phase of arthritis, the lymphatic vessels were dilated, with increased indocyanine green signal intensity and lymphatic pulses, and popliteal LNs became fluorescent quickly. During the chronic phase, new lymphatic vessels were present near the foot. However, the appearance of indocyanine green in lymphatic vessels was delayed. The size and area of popliteal LN lymphatic sinuses progressively increased in the K/BxN mice.
Our findings indicate that indocyanine green near-infrared lymphatic imaging is a valuable method for assessing the lymphatic draining function in mice with inflammatory arthritis. Indocyanine green-near-infrared imaging of K/BxN mice identified 2 distinct lymphatic phenotypes during the acute and chronic phase of inflammation. This technique can be used to assess new therapies for lymphatic disorders.
Arthritis & Rheumatism 03/2010; 62(7):1881-9. · 7.87 Impact Factor
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Dan Li,
Kirill Gromov,
Steven T Proulx,
Chao Xie,
Jie Li,
Daniel P Crane,
Kjeld Søballe,
Regis J O'Keefe,
Hani A Awad, Lianping Xing,
Edward M Schwarz
[show abstract]
[hide abstract]
ABSTRACT: The effects of antiresorptive agents (e.g., alendronate [Aln], osteoprotegerin [OPG]) on bone infection are unknown. Thus, their effects on implant-associated osteomyelitis (OM) were investigated in mice using PBS (placebo), gentamycin, and etanercept (TNFR:Fc) controls. None of the drugs affected humoral immunity, angiogenesis, or chronic infection. However, the significant (P < 0.05 vs. PBS) inhibition of cortical osteolysis and decreased draining lymph node size in Aln- and OPG-treated mice was associated with a significant (P < 0.05) increase in the incidence of high-grade infections during the establishment of OM. In contrast, the high-grade infections in TNFR:Fc-treated mice were associated with immunosuppression, as evidenced by the absence of granulomas and presence of Gram(+) biofilm in the bone marrow. Collectively, these findings indicate that although antiresorptive agents do not exacerbate chronic OM, they can increase the bacterial load during early infection by decreasing lymphatic drainage and preventing the removal of necrotic bone that harbors the bacteria.
Annals of the New York Academy of Sciences 03/2010; 1192:84-94. · 3.15 Impact Factor
