Protein Tyrosine Phosphatase Epsilon Affects Body Weight by Downregulating Leptin Signaling in a Phosphorylation-Dependent Manner

Authors

Liat Rousso-Noori, Hilla Knobler, Einat Levy-Apter, Yael Kuperman, Adi Neufeld-Cohen, Yonat Keshet, Vasudheva R. Akepati, Richard A. Klinghoffer, Alon Chen, Ari Elson

Abstract

Molecular-level understanding of body weight control is essential for combating obesity. We show that female mice lacking tyrosine phosphatase epsilon (RPTPe) are protected from weight gain induced by high-fat food, ovariectomy, or old age and exhibit increased whole-body energy expenditure and decreased adiposity. RPTPe-deficient mice, in particular males, exhibit improved glucose homeostasis. Female nonobese RPTPe-deficient mice are leptin hypersensitive and exhibit reduced circulating leptin concentrations, suggesting that RPTPe inhibits hypothalamic leptin signaling in vivo. Leptin hypersensitivity persists in aged, ovariectomized, and high-fat-fed RPTPe-deficient mice, indicating that RPTPe helps establish obesity-associated leptin resistance. RPTPe associates with and dephosphorylates JAK2, thereby downregulating leptin receptor signaling. Leptin stimulation induces phosphorylation of hypothalamic RPTPe at its C-terminal Y695, which drives RPTPe to downregulate JAK2. RPTPe is therefore an inhibitor of hypothalamic leptin signaling in vivo, and provides controlled negative-feedback regulation of this pathway following its activation.

Link to Article

http://dx.doi.org/10.1016/j.cmet.2011.02.017

Inhibition of Prostate Cancer Osteoblastic Progression with VEGF121/rGel, a Single Agent Targeting Osteoblasts, Osteoclasts, and Tumor Neovasculature

Authors

Khalid A. Mohamedali, Zhi Gang Li, Michael W. Starbuck, Xinhai Wan, Jun Yang, Sehoon Kim, Wendy Zhang, Michael G. Rosenblum, and Nora M. Navone

Abstract

A hallmark of prostate cancer (PCa) progression is the development of osteoblastic bone metastases, which respond poorly to available therapies. We previously reported that VEGF121/rGel targets osteoclast precursors and tumor neovasculature. Here we tested the hypothesis that targeting nontumor cells expressing these receptors can inhibit tumor progression in a clinically relevant model of osteoblastic PCa. Experimental Design: Cells from MDA PCa 118b, a PCa xenograft obtained from a bone metastasis in a patient with castrate-resistant PCa, were injected into the femurs of mice. Osteoblastic progression was monitored following systemic administration of VEGF121/rGel. VEGF121/rGel was cytotoxic in vitro to osteoblast precursor cells. This cytotoxicity was specific as VEGF121/rGel internalization into osteoblasts was VEGF121 receptor driven. Furthermore, VEGF121/rGel significantly inhibited PCa-induced bone formation in a mouse calvaria culture assay. In vivo, VEGF121/rGel significantly inhibited the osteoblastic progression of PCa cells in the femurs of nude mice. Microcomputed tomographic analysis revealed that VEGF121/rGel restored the bone volume fraction of tumor-bearing femurs to values similar to those of the contralateral (non–tumor-bearing) femurs. VEGF121/rGel significantly reduced the number of tumor-associated osteoclasts but did not change the numbers of peritumoral osteoblasts. Importantly, VEGF121/rGel-treated mice had significantly less tumor burden than control mice. Our results thus indicate that VEGF121/rGel inhibits osteoblastic tumor progression by targeting angiogenesis, osteoclastogenesis, and bone formation. Targeting VEGF receptor (VEGFR)-1- or VEGFR-2–expressing cells is effective in controlling the osteoblastic progression of PCa in bone. These findings provide the basis for an effective multitargeted approach for metastatic PCa.

Link to Article

http://dx.doi.org/10.1158/1078-0432.CCR-10-2943

Modification of osteoarthritis in the guinea pig with pulsed low-intensity ultrasound treatment

Authors

I. Gurkan, A. Ranganathan, X. Yang, W.E. Horton Jr., M. Todman, J. Huckle, N. Pleshko, R.G. Spencer

Abstract

The Hartley guinea pig develops articular cartilage degeneration similar to that seen in idiopathic human osteoarthritis (OA). We investigated whether the application of pulsed low-intensity ultrasound (PLIUS) to the Hartley guinea pig joint would prevent or attenuate the progression of this degenerative process. Treatment of male Hartley guinea pigs was initiated at the onset of degeneration (8 weeks of age) to assess the ability of PLIUS to prevent OA, or at a later age (12 months) to assess the degree to which PLIUS acted to attenuate the progression of established disease. PLIUS (30mW/cm2) was applied to stifle joints for 20min/day over periods ranging from 3 to 10 months, with contralateral limbs serving as controls. Joint cartilage histology was graded according to a modified Mankin scale to evaluate treatment effect. Immunohistochemical staining for interleukin-1 receptor antagonist (IL-1ra), matrix metalloproteinase (MMP)-3, MMP-13, and transforming growth factor (TGF)-β1 was performed on the cartilage to evaluate patterns of expression of these proteins. PLIUS did not fully prevent cartilage degeneration in the prevention groups, but diminished the severity of the disease, with the treated joints showing markedly decreased surface irregularities and a much smaller degree of loss of matrix staining as compared to controls. PLIUS also attenuated disease progression in the groups with established disease, although to a somewhat lesser extent as compared to the prevention groups. Immunohistochemical staining demonstrated a markedly decreased degree of TGF-β1 production in the PLIUS-treated joints. This indicates less active endogenous repair, consistent with the marked reduction in cartilage degradation. PLIUS exhibits the ability to attenuate the progression of cartilage degeneration in an animal model of idiopathic human OA. The effect was greater in the treatment of early, rather than established, degeneration.

Link to Article

http://dx.doi.org/10.1016/j.joca.2010.01.006

Proteinase-activated Receptor-2 Gene Disruption Limits the Effect of Osteoarthritis on Cartilage in Mice: A Novel Target in Joint Degradation

Authors

Nathalie Amiable, Johanne Martel-Pelletier, Bertrand Lussier, Steeve Kwan Tat, Jean-Pierre Pelletier, Christelle Boileau

Abstract

Evidence indicates that proteinase-activated receptor (PAR)-2 participates in the degradative processes of human osteoarthritis (OA). We evaluated the in vivo effect of PAR-2 on articular lesions in a PAR-2-knockout (KO) mouse model of OA. Methods.OA was surgically induced by destabilization of the medial meniscus of the right knee in C57Bl/6 wild-type (WT) and PAR-2 KO mice. Knee swelling was measured throughout the duration of the study (8 weeks postsurgery) and histologic evaluation of cartilage was done to assess structure, cellularity, matrix staining, and remodeling in the deep zone. Morphometric analysis of subchondral bone was also performed. Data showed significant knee swelling in the operated WT mice immediately following surgery, which increased with time (8 weeks post-surgery). Knee swelling was significantly lower (p ≤ 0.0001) in PAR-2 KO mice than in WT mice at both 4 and 8 weeks postsurgery. Cartilage damage was found in both operated WT and PAR-2 KO mice; however, lesions were significantly less severe (global score; p ≤ 0.05) in the PAR-2 KO mice at 4 weeks postsurgery. Operated WT mice showed reduced subchondral bone surface and trabecular thickness with significance reached at 4 weeks (p ≤ 0.03 and p ≤ 0.05, respectively), while PAR-2 KO mice demonstrated a gradual increase in subchondral bone surface with significance reached at 8 weeks (p ≤ 0.007). We demonstrated the in vivo implication of PAR-2 in the development of experimental OA, thus confirming its involvement in OA joint structural changes and reinforcing the therapeutic potential of a PAR-2 antagonist for treatment of OA.

Link to Article

http://dx.doi.org/10.3899/jrheum.100710

Enhanced osteointegration of orthopaedic implant gradient coating composed of bioactive glass and nanohydroxyapatite

Authors

Xin-Hui Xie, Xiao-Wei Yu, Shao-Xian Zeng, Rui-Lin Du, Yu-Huai Hu, Zhen Yuan, Er-Yi Lu, Ke-Rong Dai and Ting-Ting Tang

Abstract

We conducted histologic and histomorphometric studies to evaluate the osteointegration of gradient coatings composed of bioactive glass and nanohydroxyapatite (BG–nHA) on titanium-alloy orthopaedic implants and surrounding bone tissue in vivo. Titanium-alloy implants with a gradient coating (gradient coating group), uncoated implants (uncoated group), and implants with a conventional hydroxyapatite (HA) coating (HA coating group) were randomly implanted in bilateral femoral condyles of 36 male New Zealand rabbits. The bone–implant contact at 12 and 24 weeks and the new bone volume in the notch created for observing bone ingrowth at 4, 12, and 24 weeks were found greater in the gradient coating group than those in both the uncoated group and the HA coating group (p < 0.05). Fluorescence micrographs showed active osteogenesis in the gradient coating group at 4 weeks after implantation. These findings indicated that BG–nHA gradient coatings could enhance the osteointegration of orthopaedic implant.

Link to Article

http://dx.doi.org/10.1007/s10856-010-4077-6

Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

Authors

Juan Du, Binbin Cheng, Xiaoyan Zhu, Changquan Ling

Abstract

Glucocorticoids (GCs) are widely used to treat inflammatory diseases. However, they cause debilitating side effects, which limit the use of these compounds. In the past decade, many researchers have attempted to find so-called dissociated GCs that have separate distinct transactivation and transrepression activities. Anti-inflammation of GCs is a result of glucocorticoid receptor (GR)-mediated transactivation and transrepression in some tissues, similar to their side effects; therefore, the goal to discover a compound that has anti-inflammatory properties, but lacks the negative side effects seen with GCs, has yet to be achieved. In the present study, we introduce a plant-derived compound, ginsenoside Rg1, which possesses GC and estrogen-like activities. In this study, we show that Rg1 downmodulates LPS-induced proinflammatory cytokine release and inhibits NF-κB nuclear translocation and DNA binding activity. The negative effects on NF-κB activation are due to a decrease in IκB phosphorylation and protein stabilization. Furthermore, the inhibitory effect of Rg1 on NF-κB is GR-dependent, as small interfering RNA knockdown of GR abrogated this function. Rg1 also displayed profound inhibitory effects on LPS-induced MAPK activation. Importantly, Rg1 did not impair proliferation or differentiation of mouse osteoblasts. Finally, we show that Rg1 can effectively inhibit acute and chronic inflammation in vivo, but it does not cause hyperglycemia or osteoporosis as seen with dexamethasone. These results suggest that ginsenoside Rg1 may serve as a novel anti-inflammatory agent and may exhibit a potential profile for therapeutic intervention in inflammatory diseases.

Link to Article

http://www.jimmunol.org/content/early/2011/06/08/jimmunol.1002579.abstract