We recently provided evidence that mesenchymal stromal/stem cells (MSCs) are key players in synovialhyperplasia secondary to joint surface injury . First isolated from bone marrow [5, 6], MSCs were later established in vitro from several connective tissues as fibroblast-like cells with abilities to form colonies de- rived from single cells (colony-forming unit fibroblasts [CFU-F]) and to give rise to mature cells of mesenchy- mal lineages such as osteoblasts and chondrocytes . We previously reported the isolation and characterisa- tion of multipotent MSCs from the adult human synovium [8–11]. More recently, we employed a double- nucleoside analogue labelling method to demonstrate the in vivo identification and location of MSCs in the mouse synovium, and showed that following joint surface injury these cells proliferated to sustain synovialhyperplasia . Whether these proliferative MSCs in hyperplastic synovium are resident synovial cells or move into the tissue from elsewhere is not known.
While ARG098 is a new potentially effective tool for the inhibition of synovialhyperplasia and joint swelling, ARG098 could also possibly affect normal cells that express Fas on the cell surface and this may lead to adverse events during RA treatment. Then we checked the effect of ARG098 on PBMCs from the same RA patients, and on normal human chondrocytes. As results, we could not found any adverse effect of ARG098 on these cell viabilities, in vitro. In case of chondrocytes, in addition, no apoptosis or damage to RA chondrocytes was observed in ARG098-treated tis- sues during the histopathological assessment of ARG098-treated RA synovium and cartilage co- implanted in the SCID-HuRAg mice.
In this study, we analyzed whether curcumin modulates RA-induced inflammation and synovialhyperplasia and investigated the associated mechanism. We successfully established type II collagen-induced arthritis in rats and found that curcumin significantly increased the weight of rats and decreased the edema volume and arthritic score of rat hind paws. Curcumin also inhibited the mTOR pathway and the subsequent production of IL-1 β , TNF- α , MMP-1, and MMP in the serum and synovium of RA rats.
DMARDs and other biological therapies reduce syn- ovial hyperplasia, cartilage destruction, inflammatory cell infiltration, and disease activity score in RA . We found that Bi-Qi treatment at moderate dose reduced the arthritic score, inflammatory cell infiltration, synovialhyperplasia, cartilage destruction, and pannus formation as effectively as MTX treatment. Bi-Qi is very cheap in comparison to MTX. Folic acid is usually prescribed to reduce the adverse effect of MTX. In the field of TCM, the combination of different TCM plant extracts is supposed to synergistically nullify the adverse effect of each other. Bi-Qi has been formulated based on the 3000 years of practice of TCM to minimize the systemic adverse effects. However, Bi-Qi treatment has an adverse effect on the gastrointestinal tract causing diarrhoea, which was occasionally observed in the Bi-Qi-treated rats. Besides this, no other systemic adverse effects of Bi-Qi treatment were observed. However, future studies focused on the possible adverse effect of Bi-Qi in vital organs and systems are highly essential. Among major compounds of Bi-Qi, salvianolic acid B is an antioxidant, glycyrrhizin has anti-autoimmune-reactive properties, brucine is an anti-inflammtory and analgesic compound, Strychnine is a convulsant, and tanshinone IIA is active against oxidative stress . However, many other com- pounds present in Bi-Qi are still unknown. Identification of all compounds present in Bi-Qi, their metabolism and systemic adverse effects will provide the important insights to corroborate the use of Bi-Qi as a potential Table 4 Pathological features of cartilage
heumatoid arthritis (RA) is chronic, relapsing inflammatory, autoimmune disease that affects the joints. It involves numerous cell types, including macrophages, T cells, B cells, ﬁbroblasts, chondrocytes, and dendritic cells. 1 It is characterized by inflammation of the synovial membrane, cartilage and bone destruction, pain and restricted joint movement. It is a most common inflammatory arthritis affecting approximately 1-2 % of the general population worldwide. Incidences increases with age, women being affected three times more than men. 2,3 It often starts between ages 25 and 55. The disease is characterized by aggressive synovialhyperplasia (pannus formation) and inflammation (synovitis) results from immune response and non- antigen specific innate inflammatory process. That are untreated, leads to destruction of joint cartilage and bone. 3 Expansion of the synovial lining of joints and the subsequent invasion due to pannus underlying the bone and cartilage occurs in RA. To cope the increased oxygen and nutrient requirement requires an increase in the vascular supply to the synovium. RA usually affects joints on both sides of the body equally. There are different types of arthritis. Morning stiffness, joint pain etc are some of the symptoms of the RA. Risk factors for RA are age, gender, family history etc. There are various advance techniques for diagnosis of RA. There are two important components of the immune system that play a role in the inflammation associated with rheumatoid arthritis are B cells and T cells and other pro-inflammatory cytokines, chemokines and nitric oxide are also responsible for pathogenesis of RA. There are different targets for treatment of RA. Complete Freund’s adjuvant induced arthritis, Collagen type II induced arthritis are commonly used animal models to see anti-arthritic activity of a drug.
Collagen antibody induced arthritis (CAIA) experiments After injection with five anti-type II collagen monoclonal antibodies and stimulated with LPS, the arthritis scores of the control and CAIA mice were 0 points on days 1 to 5 (Fig. 2). The arthritis scores of the CAIA mice increased from days 6 to 12. The ankles of the control mice didn’t show any damage on H/E staining (Fig. 3 A: a and b). On the contrary, destruction of the cartilage and bone, synovialhyperplasia, visible articular cartilage surface roughness, local infiltration of inflammatory cells, synovialhyperplasia were observed in the CAIA mice (Fig. 3 A: c and d). Immunohis- tochemical analysis of the ankles exhibited increased expres- sion of RHAMM in the CAIA mice compared with the control mice, especially in the cartilage, bone and synovial membrane (Fig. 3 A: e, f and g, h).Expression of RHAMM was different in joints tissues, particularly in synovial tissues both in CAIA induced and control mice. Accordingly, ele- vated RHAMM expression was observed in cartilage, bone and synovial tissues compared to that in other tissues.
susceptible to PG-PS-induced acute arthritis . Intrave- nous injection of PG-PS caused polyarthritis that reached a peak at around 2 days after injection. At that time, each animal in the wild-type group had developed arthritis (19/ 19 mice [100%]), with an average arthritis index of 4.1 ± 0.5 (Fig. 4). In CD14 knockout mice, both the incidence of arthritis (11/16 [68%]; P < 0.05) and the average arthritis index (2.3 ± 0.5; P < 0.05) were significantly inhibited. The pathomorphologic changes within arthritic joints were consistent with those previously described in this model  (i.e. the infiltration of inflammatory cells into the syn- ovium, synovialhyperplasia, and fibrinous deposits; Fig. 5a). Infiltration of inflammatory cells was apparent in the tibio-tarsal joint space, synovium, tendon, toes, and sur- rounding soft tissues. Extensive deposition of fibrinous exu- date in the tibio-tarsal joint and in the bursa of the Achilles' tendon was also observed. There was neither pannus for- mation nor destruction of cartilage and subchondral bone. All of these changes were observed in some CD14 knock- out mice as well, but the magnitude of these changes was
hyperplasia, angiogenesis in inflamed synovium, pannus formation, bone erosion, and cartilage destruction. Immune features in RA were analyzed by examining immune cell populations and cytokine production. Results: BATF was upregulated in the synovial tissues of joints in which inflammatory arthritis had been caused by CIA or K/BxN serum transfer. The increases in CIA incidence, clinical score, and autoantibody production in CIA-induced WT mice were completely abrogated in the corresponding Batf −/− DBA/1 J mice. Genetic ablation of Batf also inhibited CIA-induced synovitis, synovialhyperplasia, angiogenesis in synovial tissues, pannus formation, bone erosion, and cartilage destruction. Batf knockout inhibited the differentiation of T helper (Th)17 cells and the conversion of CD4 + Foxp3 + cells to CD4 + IL-17 + cells. However, BATF did not modulate the functions of fibroblast-like synoviocytes (FLS), including the expressions of chemokines, matrix- degrading enzymes, vascular endothelial growth factor, and receptor activator of NF- κ B ligand (RANKL). Conclusion: Our findings indicate that BATF crucially mediates CIA by regulating Th cell differentiation without directly affecting the functions of FLS.
We introduce Synoviolin as a novel pathogenic factor in rheumatoid arthritis (RA). Experimental studies indicate that this endoplasmic reticulum (ER)-resident E3 ubiquitin ligase has important functions in the ER-associated degradation (ERAD) system, an essential system for ER homeostasis. Overexpression of Synoviolin in mice causes arthropathy with synovialhyperplasia, whereas heterozygous knockdown results in increased apoptosis of synovial cells and resistance to collagen-induced arthritis in mice. On the basis of these experimental data, we propose that excess elimination of unfolded proteins (that is, ‘hyper-ERAD’) by overexpression of Synoviolin triggers synovial cell overgrowth and hence a worsening of RA. Further analysis of the hyper-ERAD system may permit the complex pathomechanisms of RA to be uncovered.
Rheumatoid arthritis (RA) is an autoimmune in ﬂ ammatory disease characterized by synovialhyperplasia leading to the erosion of bones and cartilage, resulting in joint dysfunction and increased mortality rates. 1,3 RA affects about 0.5 – 1% of the world ’ s population 4,7 and its prevalence is slightly higher in Western countries as compared to Asian populations. In Pakistan the prevalence of RA is greater in northern areas in comparison to other regions. 5 RA is more common in females than males, with a ratio of 3:1. 2,8 The current treatment of RA with NSAIDs and DMARDs produces symptomatic relief and is restricted in use because of the off- targeted adverse effects. 3
development of BPH . Animal models of BPH are based on prostate overstimulation by these hormones [13, 14]. In testosterone-induced model, administration of testosterone causes hyperplasia in ventral lobes of the rat prostate, analogous to morphological changes in human BPH [15-17]. In sulpiride-induced model, sulpiride stimulates prolactin production by the pituitary gland, thus causing hyperplasia in the lateral and dorsal prostate lobes. Levels of serum prolactin are increased with age. Therefore, the sulpiride model is closely related to BPH in humans . Here we compared therapeutic effects of 5αR inhibitor Finasteride, commonly used in BPH therapy, and Rapatar in two rat models of BPH.
Synovium-derived MSCs have been shown to have im- munosuppressive properties in vitro. They have been shown to inhibit the activation and proliferation of T cells, besides being also able to induce the formation of T-reg cells [8, 21, 52]. Hagmann et al.  found that MSCs isolated from patients with osteoarthritis (OA) can retain the percentage of T-regs when co-cultured with T-reg-enriched lymphocytes from healthy donors, with IL-6 playing an important role in mediating these processes. Djouad et al.  provided the first evidence that MSCs isolated from the synovial membrane could suppress T cell response in a mixed lymphocyte reac- tion, and simultaneously expressing the indoleamine 2,3- dioxygenase (IDO) enzyme (possible mediator of this suppressive activity) to a similar extent as bone marrow MSCs. In our study of synovium-derived MSCs, we also confirmed that these cells have the effect of inhibiting the proliferation of T cells, and this inhibition is en- hanced with increasing numbers of MSCs .
FLH is recognized as a non-neoplastic proliferative lymphoid lesion and shows very uncommon features. It is also referred to as pseudolymphoma and nodular lymphoid tissue. FLH involves various organs such as the skin, orbit, nasopharynx, larynx, thyroid, lungs, gastrointestinal tract, breasts, spleen, pancreas, and liver [1, 2]. Furthermore, the sites of occurrence of FLH in the oral and maxillofacial regions have included the pal- ate, tongue, salivary gland, and cheek region [4, 5]. Adkins has initially reported the clinicopathological fea- tures of lymphoid hyperplasia in the oral mucosa in
proliferation, synovial cells were cocultured with the HTLV-I-producing T cell lines (MT-2 or HCT-1). After coculture with HTLV-I-infected T cells, the synovial cells expressed HTLV-I- specific core antigens, and HTLV-I proviral DNA was detected from the synovial cells by polymerase chain reaction. These cocultured synovial cells with HTLV-I-infected T cells proliferated more actively than the synovial cells cocultured with uninfected T cells. This stimulatory effect of HTLV-I-infected T cells on synovial cell proliferation seems necessary to contact each other. After being cocultured with MT-2 cells, synovial cells proliferated more actively than control cells even after several passages. Furthermore, HTLV-I-infected synovial cells produced significant amounts of granulocyte/macrophage colony-stimulating factor. These results suggest that HTLV-I can infect synovial cells, resulting their active proliferation and may be involved in the pathogenesis of proliferative synovitis similar to that found in rheumatoid arthritis.
Plasma miRNAs have been shown to be remarkably sta- ble in plasma and protected from endogenous RNase activity . In previous reports, plasma miRNAs are sta- ble at room temperature for up to 24 h and resistant for freeze-thawing from -80°C to room temperature up to eight times. We additionally demonstrated that miRNAs in synovial fluid were as stable as miRNAs in plasma and that both of these miRNAs were also stable at -20°C for up to seven days. These stabilities contribute to the hand- iness of plasma and synovial fluid miRNAs as biomarkers. Although we showed that synovial tissue is a main source of synovial fluid miRNA, the mechanism for sta- bility of synovial fluid miRNA remains to be determined. In plasma, some miRNAs are thought to be secreted in a form of exosomes, which are 50- to 90-nm membrane vesicles abundant in plasma containing mRNAs and miR-
The synovial disposition and the response to dexametha- sone were characterised in an equine model of synovitis after a single IA administration of DSP. The inertial sen- sor based lameness scoring system was the most sensi- tive of the methods used to evaluate the response to dexamethasone in this study. The presented quantitative information can be used as input for both future research and programs intended to upheld integrity and horse welfare in horseracing and equestrian sports. Dexa- methasone synovial fluid half-life was considered similar to that in plasma. A tentative potency and efficacy value for lameness reduction was proposed. Lameness was suppressed after treatment with dexamethasone despite doses lower than labelled doses (2–10 mg). Low doses of DSP combined with short half-life of dexamethasone in synovial fluid following IA administration will result in short duration of response, which must be considered in clinical treatment.
and malignant salivary gland tumors and the presence of intercalated duct hyperplasia around epithelial-myoepithelial carcinoma ca- ses could be interpreted as a potential precur- sor lesion. Adenomatoid ductal hyperplasia is usually an incidental microscopic finding during histologic examination of a salivary gland tumor . Yu and Donath  reported extensive ade- nomatous proliferations forming mass lesions. Sclerosing lesions of salivary glands include sclerosing polycystic adenosis, sclerosis asso- ciated with chronic sialadenitis, and sclerosing adenosis like ductal proliferation. In two of our adenomatoid ductal hyperplasia cases, there were ductal epithelial and myoepithelial proli- ferations composed of irregular and dilated ducts within a sclerotic and hyalinizing stro- ma. This appearance is quite different from those of sclerosing polycystic adenosis of sali- vary glands and sclerosing sialadenitis.
Most histopathological findings of hysterectomy specimens in present study were of benign in nature, requiring no further treatment. Evidence of simple endometrial hyperplasia without cytological atypia require no further intervention beyond hysterectomy. Hysterectomy is done commonly in most of patients, to improve their quality of life and sometimes as a lifesaving measure. Hysterectomy , like other surgeries , is also associated with a surgical risk and complications .Indication for hysterectomy , thus should be evaluated carefully prior to surgery;alternative modalities should be explored before sacrificing uterus of a patients . The possible hormonal and physiological changes after hysterectomy should be observed and managed.
citrus blend, 43% Alcohol, and 200 mg/kg Moringa for 21 days. The slide labelled citrus blend and alcohol also shows hyperplasia but on a grander scale as a result of continuous exposure of the uterus to the deleterious effects of alcohol and moringa which is combined in the Gordon’s dry gin moringa citrus blend. The slide labelled moringa also showed cystic hyperplasia which is a strong indication that continuous consumption of moringa over a period of time has effects on the uterus via direct interaction on the estrous cycle as confirmed by a previously reported study .