The Wnt/β-Catenin Pathway Interacts Differentially with PTHrP Signaling to Control Chondrocyte Hypertrophy and Final Maturation

Sequential proliferation, hypertrophy and maturation of chondrocytes are required for proper endochondral bone development and tightly regulated by cell signaling. The canonical Wnt signaling pathway acts through β-catenin to promote chondrocyte hypertrophy whereas PTHrP signaling inhibits it by holding chondrocytes in proliferating states. Here we show by genetic approaches that chondrocyte hypertrophy and final maturation are two distinct developmental processes that are differentially regulated by Wnt/β-catenin and PTHrP signaling. Wnt/β-catenin signaling regulates initiation of chondrocyte hypertrophy by inhibiting PTHrP signaling activity, but it does not regulate PTHrP expression. In addition, Wnt/β-catenin signaling regulates chondrocyte hypertrophy in a non-cell autonomous manner and Gdf5/Bmp signaling may be one of the downstream pathways. Furthermore, Wnt/β-catenin signaling also controls final maturation of hypertrophic chondrocytes, but such regulation is PTHrP signaling-independent

Biomechanical Thresholds Regulate Inflammation through the NF-κB Pathway: Experiments and Modeling

BACKGROUND: During normal physical activities cartilage experiences dynamic compressive forces that are essential to maintain cartilage integrity. However, at non-physiologic levels these signals can induce inflammation and initiate cartilage destruction. Here, by examining the pro-inflammatory signaling networks, we developed a mathematical model to show the magnitude-dependent regulation of chondrocytic responses by compressive forces. METHODOLOGY/PRINCIPAL FINDINGS: Chondrocytic cells grown in 3-D scaffolds were subjected to various magnitudes of dynamic compressive strain (DCS), and the regulation of pro-inflammatory gene expression via activation of nuclear factor-kappa B (NF-kappaB) signaling cascade examined. Experimental evidences provide the existence of a threshold in the magnitude of DCS that regulates the mRNA expression of nitric oxide synthase (NOS2), an inducible pro-inflammatory enzyme. Interestingly, below this threshold, DCS inhibits the interleukin-1beta (IL-1beta)-induced pro-inflammatory gene expression, with the degree of suppression depending on the magnitude of DCS. This suppression of NOS2 by DCS correlates with the attenuation of the NF-kappaB signaling pathway as measured by IL-1beta-induced phosphorylation of the inhibitor of kappa B (IkappaB)-alpha, degradation of IkappaB-alpha and IkappaB-beta, and subsequent nuclear translocation of NF-kappaB p65. A mathematical model developed to understand the complex dynamics of the system predicts two thresholds in the magnitudes of DCS, one for the inhibition of IL-1beta-induced expression of NOS2 by DCS at low magnitudes, and second for the DCS-induced expression of NOS2 at higher magnitudes. CONCLUSIONS/SIGNIFICANCE: Experimental and computational results indicate that biomechanical signals suppress and induce inflammation at critical thresholds through activation/suppression of the NF-kappaB signaling pathway. These thresholds arise due to the bistable behavior of the networks originating from the positive feedback loop between NF-kappaB and its target genes. These findings lay initial groundwork for the identification of the thresholds in physical activities that can differentiate its favorable actions from its unfavorable consequences on joints

Population-Based Rates of Revision of Primary Total Hip Arthroplasty: A Systematic Review

Background: Most research on failure leading to revision total hip arthroplasty (THA) is reported from single centers. We searched PubMed between January 2000 and August 2010 to identify population- or community-based studies evaluating ten-year revision risks. We report ten-year revision risk using the Kaplan-Meier method, stratifying by age and fixation technique. Results: Thirteen papers met the inclusion criteria. Cemented prostheses had Kaplan-Meier estimates of revision-free implant survival of ten years ranging from 88 % to 95%; uncemented prostheses had Kaplan-Meier estimates from 80 % to 85%. Estimates ranged from 72 % to 86 % in patients less than 60 years old and from 90 to 96 % in older patients. Conclusion: Data reported from national registries suggest revision risks of 5 to 20 % ten years following primary THA. Revision risks are lower in older THA recipients. Uncemented implants may have higher ten-year rates of revision, regardless of age

Design of Group IIA Secreted/Synovial Phospholipase A2 Inhibitors: An Oxadiazolone Derivative Suppresses Chondrocyte Prostaglandin E2 Secretion

Group IIA secreted/synovial phospholipase A2 (GIIAPLA2) is an enzyme involved in the synthesis of eicosanoids such as prostaglandin E2 (PGE2), the main eicosanoid contributing to pain and inflammation in rheumatic diseases. We designed, by molecular modeling, 7 novel analogs of 3-{4-[5(indol-1-yl)pentoxy]benzyl}-4H-1,2,4-oxadiazol-5-one, denoted C1, an inhibitor of the GIIAPLA2 enzyme. We report the results of molecular dynamics studies of the complexes between these derivatives and GIIAPLA2, along with their chemical synthesis and results from PLA2 inhibition tests. Modeling predicted some derivatives to display greater GIIAPLA2 affinities than did C1, and such predictions were confirmed by in vitro PLA2 enzymatic tests. Compound C8, endowed with the most favorable energy balance, was shown experimentally to be the strongest GIIAPLA2 inhibitor. Moreover, it displayed an anti-inflammatory activity on rabbit articular chondrocytes, as shown by its capacity to inhibit IL-1β-stimulated PGE2 secretion in these cells. Interestingly, it did not modify the COX-1 to COX-2 ratio. C8 is therefore a potential candidate for anti-inflammatory therapy in joints

Mesenchymal Stem Cell Therapy Regenerates the Native Bone-Tendon Junction after Surgical Repair in a Degenerative Rat Model

BACKGROUND: The enthesis, which attaches the tendon to the bone, naturally disappears with aging, thus limiting joint mobility. Surgery is frequently needed but the clinical outcome is often poor due to the decreased natural healing capacity of the elderly. This study explored the benefits of a treatment based on injecting chondrocyte and mesenchymal stem cells (MSC) in a new rat model of degenerative enthesis repair. METHODOLOGY: The Achilles' tendon was cut and the enthesis destroyed. The damage was repaired by classical surgery without cell injection (group G1, n = 52) and with chondrocyte (group G2, n = 51) or MSC injection (group G3, n = 39). The healing rate was determined macroscopically 15, 30 and 45 days later. The production and organization of a new enthesis was assessed by histological scoring of collagen II immunostaining, glycoaminoglycan production and the presence of columnar chondrocytes. The biomechanical load required to rupture the bone-tendon junction was determined. PRINCIPAL FINDINGS: The spontaneous healing rate in the G1 control group was 40%, close to those observed in humans. Cell injection significantly improved healing (69%, p = 0.0028 for G2 and p = 0.006 for G3) and the load-to-failure after 45 days (p<0.05) over controls. A new enthesis was clearly produced in cell-injected G2 and G3 rats, but not in the controls. Only the MSC-injected G3 rats had an organized enthesis with columnar chondrocytes as in a native enthesis 45 days after surgery. CONCLUSIONS: Cell therapy is an efficient procedure for reconstructing degenerative entheses. MSC treatment produced better organ regeneration than chondrocyte treatment. The morphological and biomechanical properties were similar to those of a native enthesis

Cartilage Breakdown in Rheumatoid Arthritis

previous Rheumatoid arthritis (RA) is a connective tissue disease characterized by destruction of the joint previous cartilage and subsequently of the underlying bone. previous Cartilagen destruction is due to proteolysis by enzymes called metalloproteinases (MMPs), whose production and expression are regulated by numerous local mediators such as cytokines, growth factors, prostaglandins, oxygen species, and neuropeptides. MMP activation is largely due to a stimulatory effect of cytokines including IL-1β and TNFα. When these cytokines bind to their membrane receptor, they set off signaling cascades, with activation of TGFβ-activating kinase (TAK-1), of NF-κB by Iκ-B kinase, of mitogen-activated protein kinases (MAP kinases), and finally of activator protein-1 (AP-1). Tissue inhibitors of MMPs (TIMPs) specifically inhibit MMPs. The interrelations between joint inflammation and joint destruction remain poorly understood. Experimental data suggest that IL-1 may be involved chiefly in joint destruction and TNF in joint inflammation. However, TNF antagonists are potent inhibitors of joint destruction in clinical practice. These results suggest that the mediators function as a network and that inhibition of a single mediator can affect the entire web. Insights gained into the innermost mechanisms of previous cartilage breakdown in patients with RA have led to major therapeutic breakthroughs. Thus, TNF antagonists have proved highly effective in RA. Future progress will no doubt stem from new knowledge about the extracellular mediators and intracellular signaling pathways that lead to the production and activation of enzymes responsible for previous cartilagenext term degradation

REVIEW OF IRSN WORK REGARDING NUCLEAR CRITICALITY ACCIDENT

International audienceThis article presents a review of the French Institute for Radiological Protection and Nuclear Safety (IRSN) work regarding nuclear criticality accidents during the last 15 years. After the separation in 2002 of the French Atomic Energy Commission (CEA) and IPSN (the latest becoming IRSN), the IRSN nuclear criticality safety department had to develop its own skills and knowledge about criticality accidents.This article will present the background and the history of the research, with the legacy of the work performed by the CEA/IPSN team in Valduc. After reminding the framework for this field, dictated by the IRSN objectives and constraints, the strategy and the various achievements accomplished by IRSN in this field will be presented. In particular, the article will cover in detail the following “phases” that can be retrospectively drawn from this global work. Initially the appropriation and the analysis of past data and tools were necessary. Then the time for the first developments, the first experiments and the first collaborations came. Next, the close connection with the dosimetry field became apparent.Finally, the perspectives and the needs for this field will be presented. It will be emphasized the need for the use of experimental facilities that can study this hazard and the need for a strong national and international collaboratio

REVIEW OF IRSN WORK REGARDING NUCLEAR CRITICALITY ACCIDENT

International audienceThis article presents a review of the French Institute for Radiological Protection and Nuclear Safety (IRSN) work regarding nuclear criticality accidents during the last 15 years. After the separation in 2002 of the French Atomic Energy Commission (CEA) and IPSN (the latest becoming IRSN), the IRSN nuclear criticality safety department had to develop its own skills and knowledge about criticality accidents.This article will present the background and the history of the research, with the legacy of the work performed by the CEA/IPSN team in Valduc. After reminding the framework for this field, dictated by the IRSN objectives and constraints, the strategy and the various achievements accomplished by IRSN in this field will be presented. In particular, the article will cover in detail the following “phases” that can be retrospectively drawn from this global work. Initially the appropriation and the analysis of past data and tools were necessary. Then the time for the first developments, the first experiments and the first collaborations came. Next, the close connection with the dosimetry field became apparent.Finally, the perspectives and the needs for this field will be presented. It will be emphasized the need for the use of experimental facilities that can study this hazard and the need for a strong national and international collaboratio