Diversity of Vascular Niches in Bones and Joints During Homeostasis, Ageing, and Diseases.

The bones and joints in the skeletal system are composed of diverse cell types, including vascular niches, bone cells, connective tissue cells and mineral deposits and regulate whole-body homeostasis. The capacity of maintaining strength and generation of blood lineages lies within the skeletal system. Bone harbours blood and immune cells and their progenitors, and vascular cells provide several immune cell type niches. Blood vessels in bone are phenotypically and functionally diverse, with distinct capillary subtypes exhibiting striking changes with age. The bone vasculature has a special impact on osteogenesis and haematopoiesis, and dysregulation of the vasculature is associated with diverse blood and bone diseases. Ageing is associated with perturbed haematopoiesis, loss of osteogenesis, increased adipogenesis and diminished immune response and immune cell production. Endothelial and perivascular cells impact immune cell production and play a crucial role during inflammation. Here, we discuss normal and maladapted vascular niches in bone during development, homeostasis, ageing and bone diseases such as rheumatoid arthritis and osteoarthritis. Further, we discuss the role of vascular niches during bone malignancy.

Anti-IL-17A treatment reduces serum inflammatory, angiogenic and tissue remodeling biomarkers accompanied by less synovial high endothelial venules in peripheral spondyloarthritis.

Spondyloarthritis (SpA) is characterized by inflammation and new bone formation. The exact pathophysiology underlying these processes remains elusive. We propose that the extensive neoangiogenesis in SpA could play a role both in sustaining/enhancing inflammation and in new bone formation. While ample data is available on effects of anti-TNF on angiogenesis, effects of IL-17A blockade on serum markers are largely unknown. We aimed to assess the impact of secukinumab (anti-IL-17A) on synovial neoangiogenesis in peripheral SpA, and how this related to changes in inflammatory and tissue remodeling biomarkers. Serum samples from 20 active peripheral SpA patients included in a 12 week open-label trial with secukinumab were analyzed for several markers of angiogenesis and tissue remodeling. Synovial biopsies taken before and after treatment were stained for vascular markers. Serum levels of MMP-3, osteopontin, IL-6 (all P < 0.001), IL-31, S100A8, S100A9, Vascular Endothelial Growth Factor A (VEGF-A), IL-33, TNF-α (all P < 0.05) decreased significantly upon anti-IL17A treatment. Secukinumab treatment resulted in a decrease in the number of synovial high endothelial venules and lymphoid aggregate score. These results indicate that anti-IL-17A not only diminishes inflammation, but also impacts angiogenesis and tissue remodeling/new bone formation. This may have important implications for disease progression and/or structural damage.

Acromegaly and joint pain: is there something more? A cross-sectional study to evaluate rheumatic disorders in growth hormone secreting tumor patients.

PURPOSE: The aim of the present study was to evaluate the rheumatic profile in acromegalic patients to better characterize joint pain. METHODS: The immunological pattern (rheumatoid factor; antinuclear antibodies-ANA, extractable nuclear antigens-ENA-Ab; anti-citrullinated protein antibodies; erythrocyte sedimentation rate) was evaluated in 20 acromegaly subjects (AS) and 20 control subjects (CS). Bilateral joint ultrasound of hands/wrists and nail capillaroscopy were also performed. RESULTS: Articular pain was more frequent in AS than in CS (p = 0.027). No difference was detected in immunological parameters. ANA and ENA-Ab were positive in only 10% of AS and in 5% of CS, while no difference was found in anti-citrullinated protein antibodies. No difference was detected between rheumatoid factor positivity, but threefold higher IgG were detected in AS compared to CS. The erythrocyte sedimentation rate was significantly higher in AS than CS (p = 0.040), while in AS, there was a trend in increased Power Doppler (PWD) articular uptake. The capillaroscopic evaluation showed a significant difference in almost each parameter (presence and number of tortuous capillaries, capillary enlargements, and hemorrhages), showing a moderate-to-severe microangiopathy in AS. CONCLUSION: The results of our study suggest that joint damage in acromegaly has not an autoimmune etiology. Increased erythrocyte sedimentation rate levels and PWD alteration in acromegalic population reflect a possible inflammatory nature, while the capillaroscopic findings suggest a moderate-to-severe microangiopathy that could help to identify patients with a greater macroangiopathic risk.

Effect of Tranexamic Acid on Hematologic Values and Blood Loss in Reverse Total Shoulder Arthroplasty.

PURPOSE: Use of tranexamic acid (TXA) in the setting of arthroplasty of the lower extremity has been previously described. The aim of this study was to evaluate the benefit of a single dose of TXA (500 mg vial) administered intravenously just prior to RTSA in an Asian population. METHODS: The records of 48 patients (no TXA, n = 24, versus TXA, n = 24) that underwent RTSA for cuff tear arthropathy were retrospectively reviewed. All patients had a Hemovac drain positioned for 2 days after surgery. Hemoglobin (Hb) and hematocrit (Hct) were checked on postoperative day 2 and compared with preoperative levels. RESULTS: Hematologic change on postoperative day 2 as determined by Hb level after surgery was statistically lower in the TXA group (2.8 ± 0.8 versus 2.1 ± 0.8 (mg/dL), P = 0.006). Mean fall in Hct level was also significantly less in the TXA group (8.0 ± 2.5 versus 6.1 ± 2.6 (L/L), P = 0.012). Total Hemovac drainage tended to be lower in the TXA group (263.4 ± 129.3 versus 203.5 ± 84.2 (ml), P = 0.064). TXA was found to have no noticeable side effects. CONCLUSION: The use of a single intravenous dose of TXA immediately prior to RTSA reduces hematologic deterioration postoperatively and the amount of Hemovac drainage. TXA could avoid unnecessary transfusion and its associated medical side effects and cost.

Insights into cryotherapy and joint bleeding: cryotherapy and hemophilia.

: There is some controversy over the use of cryotherapy. Low temperatures (Temp) could interfere with coagulation and increase the risk of bleeding. We sought to examine the effect of cryotherapy on joint swelling, temperature, friction, and inflammatory condition after experimental hemarthrosis. The left knee of 23 albino rabbits, 10 in heparin Ice, five in citrate Ice, four in heparin control, and four in citrate control were injected intraarticularly with 1 ml of blood. In total, four animals were considered to be in normal control group. Joint diameter, Temp, and ultrasonography were assessed before the blood injection. One day after the intraarticular blood injection, cryotherapy was applied 4 times per day for 4 consecutive days. Joint diameter and Temp were measured twice a day. After cessation of the protocol, joint diameter and Temp were assessed and sonography performed, animals euthanized, the friction test was performed and the synovial membrane collected, respectively. Joint diameter and Temp were increased after the intraarticular blood injection. Cryotherapy was capable of reducing the swelling and Temp. Ultrasonography findings approved the positive effect of cryotherapy on joint swelling. The proinflammatory tumor necrosis factor (TNF-α) reduced by cryotherapy in both cryotherapy groups but Interleukin 1ß was only reduced in heparin group. Interleukin-4 increased in heparin Ice group that was in comparison with TNF-α reduction. Cryotherapy reduced joint swelling and has a positive effect on controlling joint inflammation and Temp.

The Role of Angiogenesis in Haemophilic Arthropathy: Where Do We Stand and Where Are We Going?

Haemophilia is an inherited bleeding disorder that can lead to degenerative joint arthropathy due to recurrent bleeding episodes affecting the musculoskeletal system of the patient. The cause of bleeding can be either traumatic or spontaneous. The pathogenesis of haemophilic arthropathy is unclear as many factors like iron, inflammatory cytokines, and angiogenic factors contribute to this process. Blood into joints can deteriorate the bone to such an extent that the patient experiences pain, reduction of the range of movement, and deformity of the joint, conditions that could have a great impact on quality of life. Over the years, management of haemophilic arthropathy has changed. Nowadays, early diagnosis with high resolution imaging like magnetic resonance imaging along with application of prophylaxis regimens can reduce the extent of damage to the joints. However, not all haemophilia patients have access to these interventions as cost may be prohibitive for some of them. The need for new, easy, and cost-effective strategies with the ability to identify early changes could be beneficial and could make a difference in the management of haemophilic arthropathy. Understanding the mechanism of processes like angiogenesis in the mechanism of developing arthropathy could be innovative for these patients and could help in the detection of new early diagnostic and therapeutic markers.

The role of the prolactin/vasoinhibin axis in rheumatoid arthritis: an integrative overview.

Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease destroying articular cartilage and bone. The female preponderance and the influence of reproductive states in RA have long linked this disease to sexually dimorphic, reproductive hormones such as prolactin (PRL). PRL has immune-enhancing properties and increases in the circulation of some patients with RA. However, PRL also suppresses the immune system, stimulates the formation and survival of joint tissues, acquires antiangiogenic properties upon its cleavage to vasoinhibins, and protects against joint destruction and inflammation in the adjuvant-induced model of RA. This review addresses risk factors for RA linked to PRL, the effects of PRL and vasoinhibins on joint tissues, blood vessels, and immune cells, and the clinical and experimental data associating PRL with RA. This information provides important insights into the pathophysiology of RA and highlights protective actions of the PRL/vasoinhibin axis that could lead to therapeutic benefits.

Heterotopic Vascularized Joint Transfer in Mutilating Hand Injuries.

BACKGROUND: In cases of mutilating hand injuries, the primary goal is recovery of prehensile function. This is particularly true in the case of joints, which are extremely difficult to replace or reconstruct adequately when damaged. Heterotopic vascularized joint transfer is indicated when salvageable joints are available for transfer to a more functionally optimal position on the hand. MATERIALS AND METHODS: Seven cases of mutilating hand injuries treated with heterotopic vascularized joint transfers from 2003 to 2012 were retrospectively identified. All patients sustained severe metacarpophalangeal joint (MPJ) or proximal interphalangeal joint (PIPJ) damage that threatened recovery of optimal hand function. All patients were men, with an average age of 34.7 years. Operative, perioperative, and postoperative details including final active range of motion were collected and analyzed. RESULTS: Seven joints were taken from nonsalvageable amputated digits: 4 from the amputated parts, and 3 from the proximal stumps. Five joints were transferred as free flaps requiring microvascular anastomosis, and 2 were transferred on neurovascular pedicles. One joint was lost due to vasospasm. Average active range of motion was 68.3° for homojoint transfers (MPJ to MPJ, PIPJ to PIPJ), and 35° for heterojoint transfers. All but 1 patient were able to achieve tripod pinch; the remaining patient achieved only side-to-side pinch. CONCLUSIONS: Heterotopic vascularized joint transfer is a useful technique to consider in cases of mutilating hand injuries. Improved recovery of prehensile function can be achieved with thoughtful design and execution, followed by proper patient education and rehabilitation.

[The substantiation for the application of high-intensity laser therapy for the treatment of the patients presenting with gonarthrosis].

UNLABELLED: The objective of the present study was to evaluate the influence of high-intensity laser irradiation on the state of microcirculation in the patients presenting with gonarthrosis. MATERIAL AND METHODS: It included 40 patients with this condition at the ag from 40 to 75 years who were randomly allocated to two groups. Group 1 was comprised of 20 patients treated by high-intensity laser irradiation (HILl), the patients of group 2 (n = 20) underwent the placebo treatment. RESULTS: It was shown that high-intensity laser irradiation is an effective pathogenetically sound method for the management of the patients with gonarthrosis. The mechanism of enhancement of its clinical effectiveness consists of the correction of local blood circulation that accounts for the anti-inflammatory effect, decreased destruction of the connective tissue, and the improvement of the locomotor function of the affected joints.

Lithothamnion muelleri treatment ameliorates inflammatory and hypernociceptive responses in antigen-induced arthritis in mice.

Rheumatoid Arthritis (RA) is a chronic disease characterized by persistent inflammation and pain. Alternative therapies to reduce these symptoms are needed. Marine algae are valuable sources of diverse bioactive compounds. Lithothamnion muelleri (Hapalidiaceae) is a marine algae with anti-inflammatory, antitumor, and immunomodulatory properties. Here, we investigated the potential anti-inflammatory and analgesic activities of L. muelleri in a murine model of antigen-induced arthritis (AIA) in mice. Our results demonstrate that treatment with L. muelleri prevented inflammation and hypernociception in arthritic mice. Mechanistically, the crude extract and the polysaccharide-rich fractions of L. muelleri may act impairing the production of the chemokines CXCL1 and CXCL2, and consequently inhibit neutrophil influx to the knee joint by dampening the adhesion step of leukocyte recruitment in the knee microvessels. Altogether our results suggest that treatment with L.muelleri has a potential therapeutic application in arthritis treatment.

Antiarthritis Effect of Morin is Associated with Inhibition of Synovial Angiogensis.

Morin, a flavonoid isolated from Morus alba L. (Moraceae), possesses anti-inflammatory, antiangiogenic among other biological activities. This study investigated its effect on type II collagen-induced arthritis (CIA) in rats and explored the underlying mechanisms in view of synovial angiogenesis. Morin administered po attenuated arthritic progression as indicated by reduction of arthritis scores and paw swelling. It also markedly reduced serum levels of the proinflammatory cytokines, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), but increased the level of anti-inflammatory cytokine interleukin-10, and ameliorated histopathological changes of joints. Morin markedly inhibited expression of CD31, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor in synovial membrane tissues, and decreased serum levels of VEGF in CIA rats. In vitro, morin markedly inhibited VEGF-induced migration and tube formation in human umbilical vein endothelial cells. These results indicate that morin had antirheumatoid potential, and its mechanism might be associated with inhibition of synovial angiogenesis.

Characterising the expression and function of CCL28 and its corresponding receptor, CCR10, in RA pathogenesis.

OBJECTIVE: This study was conducted to determine the expression pattern, regulation and function of CCL28 and CCR10 in rheumatoid arthritis (RA) pathogenesis. METHODS: Expression of CCL28 and CCR10 was assessed in RA compared with other arthritis synovial tissues (STs) or fluids (SFs) by histology or ELISA. The factors modulating CCL28 and CCR10 expression were identified in RA myeloid and endothelial cells by ELISA, FACS and Western blotting. The mechanism by which CCL28 ligation promotes RA angiogenesis was examined in control and CCR10-knockdown endothelial cell chemotaxis and capillary formation. RESULTS: CCL28 and/or CCR10 expression levels were accentuated in STs and SFs of patients with joint disease compared with normal controls and they were predominately coexpressed in RA myeloid and endothelial cells. We show that protein expression of CCL28 and CCR10 was modulated by tumour necrosis factor (TNF)-α and toll-like receptor 4 ligation in RA monocytes and endothelial cells and by interleukin (IL)-6 stimulation in RA macrophages. Neutralisation of CCL28 in RA SF or blockade of CCR10 on human endothelial progenitor cells (EPCs) significantly reduced SF-induced endothelial migration and capillary formation, demonstrating that ligation of joint CCL28 to endothelial CCR10+ cells is involved in RA angiogenesis. We discovered that angiogenesis driven by ligation of CCL28 to CCR10 is linked to the extracellular signal regulated kinase (ERK) cascade, as CCR10-knockdown cells exhibit dysfunctional CCL28-induced ERK signalling, chemotaxis and capillary formation. CONCLUSIONS: The overexpression of CCL28 and CCR10 in RA ST and their contribution to EPC migration into RA joints support the CCL28/CCR10 cascade as a potential therapeutic target for RA.

Improving the extensor lag and range of motion following free vascularized joint transfer to the proximal interphalangeal joint: Part 2. A clinical series.

BACKGROUND: Free vascularized joint transfer for reconstructing the posttraumatic proximal interphalangeal joint has enjoyed limited popularity because of the low range of motion typically achieved after transfer. One of the commonest complaints is the significant extensor lag. Part 2 of this two-part study is focused on the clinical outcomes following a more anatomical approach to extensor tendon reconstruction. METHODS: Nine patients (eight male and one female), with a mean age of 31.7 years, underwent free vascularized joint transfer for posttraumatic proximal interphalangeal joint injuries using the second toe proximal interphalangeal joint. In Part 1, two arrangements of the central slip mechanism were found: type I with an attenuated and type II with a distinct central slip. An algorithm was constructed using this information: in a type I toe with sufficient recipient lateral bands, a centralization procedure was carried out; and when the lateral bands were insufficient, a modified Stack procedure was carried out. In type II toe joints, a tight repair of the corresponding extensor tendons was performed. RESULTS: Four patients underwent centralization procedures, two underwent a modified Stack procedure, and three underwent tight extensor repair. At 23.4 months, the average extensor lag was 18.3 degrees. A total range of motion of 53.9 degrees (mean flexion, 72.2 degrees) was achieved that approximated 81.1 percent of the pretransfer passive range of motion at the toe proximal interphalangeal joint. CONCLUSION: This preliminary result demonstrates that much improved range of motion can be achieved by reducing the extensor lag using an anatomical reconstruction that takes into account the recipient finger and toe joint anatomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The role of microparticles in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus.

Microparticles (MPs) are small membrane-bound vesicles with potent biological activities that can promote the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus (SLE). These particles contain diverse cellular components and are shed from cells during apoptosis or activation. MPs can drive inflammation and autoimmunity by multiple mechanisms reflecting their content of bioactive molecules and ability to engage multiple receptor systems simultaneously. In the rheumatoid joint, particles can stimulate synovitis via their display of cytokines, chemokines, complement and angiogenesis factors. In SLE, particles can serve as an important source of extracellular nuclear molecules to signal 'danger' and form pathogenic immune complexes. Future studies will define the pathways by which particles promote pathogenesis, strategies to block their activity and their utility as biomarkers to assess disease activity and the response to therapy.

The immunoreceptor tyrosine-based activation motif (ITAM) -related factors are increased in synovial tissue and vasculature of rheumatoid arthritic joints.

INTRODUCTION: The immunoreceptor tyrosine-based activation motif (ITAM) pathway provides osteoclast co-stimulatory signals and regulates proliferation, survival and differentiation of effector immune cells. In the osteoclast, the receptors Triggering Receptor Expressed on Myeloid cells 2 (TREM2) and Osteoclast Associated Receptor (OSCAR) and their respective adaptor proteins, DAP12 and FcRγ mediate ITAM signals and induce calcium signaling and the crucial transcription factor, NFATc1. In rheumatoid arthritis (RA), OSCAR expression by monocytes is inversely correlated with disease activity. Additionally, serum levels of OSCAR are reduced in RA patients versus healthy controls suggesting that expression and secretion or cleavage of soluble (s) OSCAR is immune modulated. Recent data suggest that endothelial cells may also be a source of OSCAR. METHODS: ITAM receptors, their adaptor proteins, and NFATc1 and cathepsin K were detected in human synovial tissues by immunohistochemistry. Synovial tissues from patients with active RA were compared with tissue from patients in remission, osteoarthritis (OA) patients and healthy individuals. OSCAR was measured by immunoassay in synovial fluids recovered from active RA and OA patients. Endothelial cells were cultured with or without 5 ng/mL TNF-α or IL-1ß over 72 hours. Temporal expression of OSCAR mRNA was assessed by qRT PCR and OSCAR protein in the supernatant was measured by ELISA. RESULTS: Significantly higher (P < 0.05) NFATc1-positive inflammatory cell aggregates were found in active RA tissues than in healthy synovial tissue. Similarly, the percentage of OSCAR, FcRγ, DAP12 and TREM2 positive cells was significantly higher in active RA tissues compared to the healthy synovial tissue. Notably, OSCAR was strongly expressed in the microvasculature of the active RA tissues (9/9), inactive RA (8/9) weakly in OA (4/9) but only in the lumen of healthy synovial tissue (0/8). OSCAR levels were detected in synovial fluids from both RA (47 to 152 ng/mL) and OA (112 to 145 ng/mL) patients. Moreover, OSCAR mRNA expression and soluble OSCAR release was stimulated by TNF-α and IL1-ß in cultured endothelial cells. CONCLUSIONS: Increased levels of ITAM related factors were present in synovial tissue from active RA joints compared to OA and healthy joints. OSCAR was strongly expressed by the vasculature of active RA patients and membrane bound and soluble OSCAR was stimulated by inflammatory mediators in endothelial cells in vitro.

Pathogenetic overview of psoriatic disease.

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease with both autoimmune and autoinflammatory features. Evidence supports the distinct nature of PsA regarding its clinical, genetic, immunohistochemical, and imaging features. Such features can help to distinguish PsA from other common rheumatic diseases. Apart from peripheral joint involvement, the musculoskeletal lesions in PsA include enthesitis and involvement of the distal interphalangeal joint (frequently associated with nail involvement, dactylitis, and axial involvement). The traditional model of pathogenesis in PsA has identified it as an autoimmune disease; however, an alternative model classifies it as having autoinflammatory features. Similarly, there are important new genetic observations focusing on the HLA region, and genome-wide association that confirms the genetic heterogeneity of patients with psoriasis and patients with PsA. Newer imaging techniques have also provided a much more detailed characterization of tissue abnormalities, in particular highlighting the extent of new bone formation, which is quite distinct from rheumatoid arthritis.

Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints.

Osteoarthritis (OA) is a degenerative joint disease and one of the leading causes of disability in the United States and across the world. As a disease of the whole joint, OA exhibits a complicated etiology with risk factors including, but not limited to, ageing, altered joint loading, and injury. Subchondral bone is hypothesized to be involved in OA development. However, direct evidence supporting this is lacking. We previously detected measurable transport of solute across the mineralized calcified cartilage in normal joints, suggesting a potential cross-talk between subchondral bone and cartilage. Whether this cross-talk exists in OA has not been established yet. Using two models that induced OA by either ageing or surgery (destabilization of medial meniscus, DMM), we tested the hypothesis that increased cross-talk occurs in OA. We quantified the diffusivity of sodium fluorescein (mol. wt. 376Da), a marker of small-sized signaling molecules, within calcified joint matrix using our newly developed fluorescence loss induced by photobleaching (FLIP) method. Tracer diffusivity was found to be 0.30±0.17 and 0.33±0.20µm(2)/s within the calcified cartilage and 0.12±0.04 and 0.07±0.03µm(2)/s across the osteochondral interface in the aged (20-24-month-old, n=4) and DMM OA joints (5-month-old, n=5), respectively, which were comparable to the control values for the contralateral non-operated joints in the DMM mice (0.48±0.13 and 0.12±0.06µm(2)/s). Although we did not detect significant changes in tissue matrix permeability in OA joints, we found i) an increased number of vessels invading the calcified cartilage (and sometimes approaching the tidemark) in the aged (+100%) and DMM (+50%) joints relative to the normal age controls; and ii) a 60% thinning of the subchondral bone and calcified cartilage layers in the aged joints (with no significant changes detected in the DMM joints). These results suggested that the capacity for cross-talk between subchondral bone and articular cartilage could be elevated in OA. Further studies are needed to identify the direction of the cross-talk, the signaling molecules involved, and to test whether subchondral bone initiates OA development and could serve as a pharmaceutical target for OA treatment. This article is part of a Special Issue entitled "Osteoarthritis".

Selective targeted delivery of the TNF-alpha receptor p75 and uteroglobin to the vasculature of inflamed tissues: a preliminary report.

BACKGROUND: Ligand-targeted approaches have proven successful in improving the therapeutic index of a number of drugs. We hypothesized that the specific targeting of TNF-alpha antagonists to inflamed tissues could increase drug efficacy and reduce side effects. RESULTS: Using uteroglobin (UG), a potent anti-inflammatory protein, as a scaffold, we prepared a bispecific tetravalent molecule consisting of the extracellular ligand-binding portion of the human TNF-alpha receptor P75 (TNFRII) and the scFv L19. L19 binds to the ED-B containing fibronectin isoform (B-FN), which is expressed only during angiogenesis processes and during tissue remodeling. B-FN has also been demonstrated in the pannus in rheumatoid arthritis. L19-UG-TNFRII is a stable, soluble homodimeric protein that maintains the activities of both moieties: the immuno-reactivity of L19 and the capability of TNFRII to inhibit TNF-alpha. In vivo bio-distribution studies demonstrated that the molecule selectively accumulated on B-FN containing tissues, showing a very fast clearance from the blood but a very long residence time on B-FN containing tissues. Despite the very fast clearance from the blood, this fusion protein was able to significantly improve the severe symptomatology of arthritis in collagen antibody-induced arthritis (CAIA) mouse model. CONCLUSIONS: The recombinant protein described here, able to selectively deliver the TNF-alpha antagonist TNFRII to inflamed tissues, could yield important contributions for the therapy of degenerative inflammatory diseases.

Tissue formation and vascularization in anatomically shaped human joint condyle ectopically in vivo.

Scale-up of bioengineered grafts toward clinical applications is a challenge in regenerative medicine. Here, we report tissue formation and vascularization of anatomically shaped human tibial condyles ectopically with a dimension of 20 x 15 x 15 mm(3). A composite of poly-epsilon-caprolactone and hydroxyapatite was fabricated using layer deposition of three-dimensional interlaid strands with interconnecting microchannels (400 microm) and seeded with human bone marrow stem cells (hMSCs) with or without osteogenic differentiation. An overlaying layer (1 mm deep) of poly(ethylene glycol)-based hydrogel encapsulating hMSCs or hMSC-derived chondrocytes was molded into anatomic shape and anchored into microchannels by gel infusion. After 6 weeks of subcutaneous implantation in athymic rats, hMSCs generated not only significantly more blood vessels, but also significantly larger-diameter vessels than hMSC-derived osteoblasts, although hMSC-derived osteoblasts yielded mineralized tissue in microchannels. Chondrocytes in safranin-O-positive glycosaminoglycan matrix were present in the cartilage layer seeded with hMSC-derived chondrogenic cells, although significantly more cells were present in the cartilage layer seeded with hMSCs than hMSC-derived chondrocytes. Together, MSCs elaborate substantially more angiogenesis, whereas their progenies yield corresponding differentiated tissue phenotypes. Scale up is probable by incorporating a combination of stem cells and their progenies in repeating modules of internal microchannels.

Scopolin isolated from Erycibe obtusifolia Benth stems suppresses adjuvant-induced rat arthritis by inhibiting inflammation and angiogenesis.

Despite scopolin is a main coumarin constituent in the stems of Erycibe obtusifolia Benth, a herb drug that has long been utilized in traditional Chinese medicine for the treatment of rheumatoid arthritis, little information is available about the pharmacological activities of this compound. The present study was performed to investigate the anti-rheumatic effects of scopolin in adjuvant-induced arthritis (AIA) in rats, and explore the underlying mechanisms of action in views of anti-inflammatory and anti-angiogenic properties in the synovial tissues. Scopolin (50, 100 mg/kg), injected intraperitoneally for 10 days from the onset of secondary response, significantly inhibited both inoculated and non-inoculated paw swelling as well as articular index scores in AIA. Meanwhile, the mean body weight of rats treated with scopolin was higher than that of model group. Rats treated with high dose of scopolin (100 mg/kg) preserved a nearly normal histological architecture of the joints and showed a significant reduction of the new blood vessels in the synovial tissues. Additionally, scopolin could reduce IL-6, VEGF and FGF-2 expressions in rat synovial tissues. In conclusion, scopolin can reduce the clinical symptoms of rat AIA by inhibiting inflammation and angiogenesis, and this compound may be a potent agent for angiogenesis related diseases and can serve as a structural base for screening more potent synthetic analogs.