Effects of triangle grass decoction on bone metabolism in rats with chronic kidney disease complicated with mineral and bone abnormalities.

ETHNOPHARMACOLOGICAL RELEVANCE: Triangle grass is a liliaceous Chlorophytum perennial herb of ChlorophytumlaxumR.Br. It is distributed mainly in Guangdong and Guangxi Provinces of China. The initial use of triangle grass was mainly to treat bone pain and swelling caused by a fall injury. Triangle grass tablets (NO. Z20070544) are also used as a preparation in our hospital because of their analgesic, anti-inflammatory, anti-snake venom and microcirculation improvement properties and other pharmacological effects (Mei et al., 2006). Triangle grass tablets have been widely used in our hospital to treat patients with bone pain from chronic kidney disease-mineral and bone disorder (CKD-MBD). However, the effects and mechanism of triangle grass on bone metabolism in chronic kidney disease complicated with mineral and bone abnormalities are unclear. AIM OF THE STUDY: The aim of the present study was to investigate the effects of a triangle grass decoction on bone metabolism in CKD-MBD rats. MATERIALS AND METHODS: CKD-MBD model rats were subjected to 5/6 nephrectomy combined with 0.5 g NaH2PO4/rat. Serum blood urea nitrogen (BUN), creatinine (Cr), phosphorus (P), calcium (Ca), and intact parathyroid hormone (iPTH) levels were measured with an automatic biochemical analyser. Bone mineral density was determined with a Viva CT 40 system. Bone morphogenetic protein 7(BMP-7),runt-related transcription factor 2 (Runx2) and Osterix protein levels were measured by Western blot analysis. Kidney, vertebra and thoracic aorta tissue samples were assessed by histopathology and immunohistochemistry (IHC). RESULTS: The degrees of membrane thickening, necrosis, swelling and cast deposition were significantly reduced in high-dose rats and Low-dose rats. Serum BUN levels were significantly reduced in the Pre-H group (P < 0.05). Hypocalcaemia and hyperphos phataemia were detected in triangle grass (P < 0.05, P < 0.05). In addition, iPTH levels were significantly increased in the Pre-H group (P < 0.05). Alkaline phosphatase (ALP)levels were significantly decreased in the Pre-H group (P < 0.05). The bone mineral density was improved in the Pre-H and Pre-L groups. BMP-7 protein levels were significantly increased in the Pre-H group (P < 0.05). The pathological changes in muscle fibres in the thoracic aorta middle membranes were significantly alleviated in rats in the Pre-H and Pre-L groups. Changes in SM22α and SMα-act in protein levels were significantly attenuated in the Pre-H group (P < 0.05, P < 0.05). Changes in Runx2 and Osterix protein levels were also significantly attenuated in the Pre-H and Pre-L groups (P < 0.05, P < 0.05). CONCLUSIONS: Triangle grass can simultaneously ameliorate vertebral bone loss and abnormal calcification in the thoracic aorta. Triangle grass has a definite effect on bone metabolism disorder in CKD-MBD rats.

Manjarix attenuated pain and joint swelling in a rat model of monosodium iodoacetate-induced osteoarthritis.

Osteoarthritis (OA) is a joint disease characterized by degeneration of cartilage, intra-articular inflammation, remodeling of subchondral bone and joint pain. The present study was designed to assess the therapeutic effects and the possible underlying mechanism of action of Manjarix, a herbal combination composed of ginger and turmeric powder extracts, on chemically induced osteoarthritis in rats. An OA model was generated by intra-articular injection of 50 µL (40 mg mL-1) of monosodium iodoacetate (MIA) into the right knee joint of rats. After one week of osteoarthritis induction, a comparison of the anti-inflammatory efficacy of indomethacin at an oral dose of 2 mg kg-1 daily for 4 successive weeks versus five decremental dose levels of Manjarix (1000, 500, 250, 125, and 62.5 mg kg-1) was performed. Serum inflammatory cytokines, interleukin 6, interleukin 8, and tumor necrosis factor alpha; C-telopeptide of type II collagen (CTX-II) and hyaluronic acid (HA) were measured, along with weekly assessment of the knee joint swelling. Pain-like behavior was assessed and knee radiographic and histological examination were performed to understand the extent of pain due to cartilage degradation. Manjarix significantly reduced the knee joint swelling, decreased the serum levels of IL6, TNF-α, CTX-II and HA, and reduced the pathological injury in joints, with no evidence of osteo-reactivity in the radiographic examination. Manjarix also significantly prevented MIA-induced pain behavior. These results demonstrate that Manjarix exhibits chondroprotective effects and can inhibit the OA pain induced by MIA, and thus it can be used as a potential therapeutic product for OA.

The role of selenium metabolism and selenoproteins in cartilage homeostasis and arthropathies.

As an essential nutrient and trace element, selenium is required for living organisms and its beneficial roles in human health have been well recognized. The role of selenium is mainly played through selenoproteins synthesized by the selenium metabolic system. Selenoproteins have a wide range of cellular functions including regulation of selenium transport, thyroid hormones, immunity, and redox homeostasis. Selenium deficiency contributes to various diseases, such as cardiovascular disease, cancer, liver disease, and arthropathy-Kashin-Beck disease (KBD) and osteoarthritis (OA). A skeletal developmental disorder, KBD has been reported in low-selenium areas of China, North Korea, and the Siberian region of Russia, and can be alleviated by selenium supplementation. OA, the most common form of arthritis, is a degenerative disease caused by an imbalance in matrix metabolism and is characterized by cartilage destruction. Oxidative stress serves as a major cause of the initiation of OA pathogenesis. Selenium deficiency and dysregulation of selenoproteins are associated with impairments to redox homeostasis in cartilage. We review the recently explored roles of selenium metabolism and selenoproteins in cartilage with an emphasis on two arthropathies, KBD and OA. Moreover, we discuss the potential of therapeutic strategies targeting the biological functions of selenium and selenoproteins for OA treatment.

Extracellular Vesicles in Joint Disease and Therapy.

The use of extracellular vesicles (EVs) as a potential therapy is currently explored for different disease areas. When it comes to the treatment of joint diseases this approach is still in its infancy. As in joint diseases both inflammation and the associated articular tissue destruction are important factors, both the immune-suppressive and the regenerative properties of EVs are potentially advantageous characteristics for future therapy. There is, however, only limited knowledge on the basic features, such as numerical profile and function, of EVs in joint articular tissues in general and their linking medium, the synovial fluid, in particular. Further insight is urgently needed in order to appreciate the full potential of EVs and to exploit these in EV-mediated therapies. Physiologic joint homeostasis is a prerequisite for proper functioning of joints and we postulate that EVs play a key role in the regulation of joint homeostasis and hence can have an important function in re-establishing disturbed joint homeostasis, and, in parallel, in the regeneration of articular tissues. In this mini-review EVs in the joint are explained from a historical perspective in both health and disease, including the potential niche for EVs in articular tissue regeneration. Furthermore, the translational potential of equine models for human joint biology is discussed. Finally, the use of MSC-derived EVs that is recently gaining ground is highlighted and recommendations are given for further EV research in this field.

Phytomedicine in Joint Disorders.

Chronic joint inflammatory disorders such as osteoarthritis and rheumatoid arthritis have in common an upsurge of inflammation, and oxidative stress, resulting in progressive histological alterations and disabling symptoms. Currently used conventional medication (ranging from pain-killers to biological agents) is potent, but frequently associated with serious, even life-threatening side effects. Used for millennia in traditional herbalism, medicinal plants are a promising alternative, with lower rate of adverse events and efficiency frequently comparable with that of conventional drugs. Nevertheless, their mechanism of action is in many cases elusive and/or uncertain. Even though many of them have been proven effective in studies done in vitro or on animal models, there is a scarcity of human clinical evidence. The purpose of this review is to summarize the available scientific information on the following joint-friendly medicinal plants, which have been tested in human studies: Arnica montana, Boswellia spp., Curcuma spp., Equisetum arvense, Harpagophytum procumbens, Salix spp., Sesamum indicum, Symphytum officinalis, Zingiber officinalis, Panax notoginseng, and Whitania somnifera.

Wnt5a is expressed in spondyloarthritis and exerts opposite effects on enthesis and bone in murine organ and cell cultures.

Spondyloarthritis (SpA) is a chronic inflammatory joint disorder that initiates at the enthesis, where tendons attach to bone through a fibrocartilage zone. At late stages, excessive bone apposition appears within the diseased enthesis. Because Wnt5a participates to normal bone formation and appears related to inflammatory processes, we investigated the role of this Wnt growth factor in inflammation-associated ossification in SpA. The concentration of Wnt5a assessed by enzyme-linked immunosorbent assay in synovial fluids of patients with SpA (2.58 ± 0.98 ng/mL) was higher than in osteoarthritic patients (1.33 ± 0.71 ng/mL). In murine primary cultures of tendon cells, chondrocytes, and osteoblasts and in an organotypic model of mouse ankle, we showed that tumor necrosis factor α reversibly diminished Wnt5a expression and secretion, respectively. Wnt5a decreased gene expression of differentiation markers and mineralization in cultured chondrocytes and reduced alkaline phosphatase activity in Achilles tendon enthesis (-14%) and osteocalcin protein levels released by ankle explants (-36%). On the contrary, Wnt5a stimulated ossification markers' expression in cultured osteoblasts and increased the bone volume of the tibial plateau of the cultured explants (+19%). In conclusion, our results suggest that Wnt5a is expressed locally in the joints of patients with SpA. Wnt5a appears more associated with ossification than with inflammation and tends to inhibit mineralization in chondrocytes and enthesis, whereas it seems to favor the ossification process in osteoblasts and bone. Further studies are needed to decipher the opposing effects observed locally in enthesis and systemically in bone in SpA.

[Effects of Yiqi Huayu prescription on knee cartilage degeneration in HIF-1alpha gene knockout mice].

OBJECTIVE: To study the role of hypoxia-inducible factor 1 alpha (HIF1alpha) on knee cartilage degeneration,and to explore the effects and mechanisms of Chinese herbal compound Yiqi Huayu prescription on HIF-1alpha gene knockout mice on knee cartilage degeneration. METHODS: The 4-month and 6-month HIF-1alpha gene knock out mice were obtained by interbreeding, and divided into HIF-1alpha +/+ 4-month mice group,HIF-1alpha -/- 4-month mice group,HIF-1alpha +/+ 6-month mice group and HIF-1alpha -/- 6-month mice group, 3 mice in each group. And then the 2-month-old HIF-1alpha gene knock out mice were randomly divided into Yiqi Huayu prescription group and physiological saline group. There were 6 mice in each group. After 2 months' drug administration, the knee joint of mice was collected, and the Mankin score were evaluated; Safranine-fast green staining, HE Staining, and immunohistochemistry analysis for VEGF, Col X, Col II, MMP-13 and Sox-9 were performed erespectively. RESULTS: (1) Compared to the results in the HIF-1alpha+/+ mice groups, the HIF-1alpha-/- mice developed aging related cartilage loss and bony tissue appearance, cartilage defects increased,and cells reduced. In HIF-1alpha-/-4-month mice and 6-month mice group, the expresion of Col II and Sox9 decreased, and the expression of Col X, MMP-13 and VEGF increased. (2) Compared to the physiological saline group, the ossification and defect of knee joint cartilage reduced of mice in the Yiqi Huayu prescription group, the cartilage cell distribution was more uniform, and the total number of cells increased. The expression of type II collagen and Sox9 protein increased, expression of Col X, MMP-13 and VEGF protein decreased of mice in the Yiqi Huayu prescription group. CONCLUSION: The knee cartilage degenerates in the HIF-1alpha cKO mice, and the degeneration increased with age adding. The Yiqi Huayu prescription can delay the degeneration of knee cartilage of HIF-1alpha cKO mice.

The "bone morphogenic proteins" pathways in bone and joint diseases: translational perspectives from physiopathology to therapeutic targets.

A large body of evidence supports an important role of bone morphogenic proteins (BMPs) pathways in skeletal development in the embryo. BMPs are also involved in skeletal homeostasis and diseases in the adult. They were first identified as major bone anabolic agents and recent advances indicate that they also regulate osteoclastogenesis and joint components via multiple cross-talks with other signaling pathways. This review attempts to integrate these data in the pathogenesis of bone and joints diseases, such as osteoporosis, fracture healing, osteoarthritis, inflammatory arthritis, or bone metastasis. The use of recombinant BMPs in bone tissue engineering and in the treatment of skeletal diseases, or future therapeutic strategies targeting BMPs signal and its regulators, will be discussed based on these considerations.

Tenascin-C levels in synovial fluid are elevated after injury to the human and canine joint and correlate with markers of inflammation and matrix degradation.

OBJECTIVE: We have previously shown the capacity of tenascin-C (TN-C) to induce inflammatory mediators and matrix degradation in vitro in human articular cartilage. The objective of the present study was to follow TN-C release into knee synovial fluid after acute joint injury or in joint disease, and to correlate TN-C levels with markers of cartilage matrix degradation and inflammation. METHOD: Human knee synovial fluid samples (n = 164) were from a cross-sectional convenience cohort. Diagnostic groups were knee healthy reference, knee anterior cruciate ligament rupture, with or without concomitant meniscus lesions, isolated knee meniscus injury, acute inflammatory arthritis (AIA) and knee osteoarthritis (OA). TN-C was measured in synovial fluid samples using an enzyme-linked immunosorbent assay (ELISA) and results correlated to other cartilage markers. TN-C release was also monitored in joints of dogs that underwent knee instability surgery. RESULTS: Statistically significantly higher levels of TN-C compared to reference subjects were observed in the joint fluid of all human disease groups and in the dogs that underwent knee instability surgery. Statistically significant correlations were observed between the TN-C levels in the synovial fluid of the human patients and the levels of aggrecanase-dependent Ala-Arg-Gly-aggrecan (ARG-aggrecan) fragments and matrix metalloproteinases 1 and 3. CONCLUSIONS: We find highly elevated levels of TN-C in human knee joints after injury, AIA or OA that correlated with markers of cartilage degradation and inflammation. TN-C in synovial fluid may serve dual roles as a marker of joint damage and a stimulant of further joint degradation.

Evaluation of serum trace mineral, vitamin D, and sex steroid hormone concentration, and survey data in llamas and alpacas with metacarpophalangeal and metatarsophalangeal hyperextension.

OBJECTIVE: To characterize serum trace mineral, sex steroid hormone, and vitamin D concentrations and identify factors associated with metacarpophalangeal and metatarsophalangeal hyperextension in llamas and alpacas. SAMPLES: Serum samples from 79 llamas and 15 alpacas and owner survey data for 573 llamas and 399 alpacas. PROCEDURES: Serum samples were stored at -20°C until analysis and were evaluated for trace mineral, vitamin D, estradiol, progesterone, and testosterone concentrations. Information regarding age of onset, number of affected animals in herd, feed and supplements given, type of housing, and management practices was obtained in an owner survey. RESULTS: Higher serum zinc and iron concentrations were associated with metacarpophalangeal and metatarsophalangeal hyperextension in camelids, compared with controls. In summer and fall months, vitamin D concentrations were significantly higher in affected camelids than controls. Overall prevalence was 13.3% in llamas, compared with 0.7% in alpacas. No management factors were found to be predictive of this condition. No other factors examined were associated with metacarpophalangeal and metatarsophalangeal hyperextension. CONCLUSIONS AND CLINICAL RELEVANCE: Despite similar supplementation practices and environmental conditions between affected and unaffected animals, an association of high serum zinc, iron, and vitamin D concentrations in affected camelids, compared with controls, may indicate differences of intake or absorption of dietary supplements.

Kirenol exerts a potent anti-arthritic effect in collagen-induced arthritis by modifying the T cells balance.

Rheumatoid arthritis is characterized by the imbalance of T cells, which leads to increased pro-inflammatory and reduced anti-inflammatory cytokines. Modulating the balance among T cells is crucial for the treatment of RA. Kirenol is a major diterpenoid components of Herba Siegesbeckiae, which has been applied for arthritic therapy for centuries. Since prior research showed Kirenol exhibited anti-inflammatory effect in rats, in this study we have evaluated the effect and mechanism of bioactive Kirenol in a rat model of collagen-induced arthritis (CIA) on modulation of T cells. After immunization with bovine type II collagen (CII), Wistar rats were orally administered saline (CIA group), 2 mg/kg Kirenol or 2 mg/kg prednisolone daily for 30 days. The severity of arthritis was clinically and histologically assessed. The numbers of CD4⁺CD25⁺Foxp3⁺ T regulatory cells (Tregs) and IFNγ⁺CD4⁺ and IL4⁺CD4⁺ T cells were determined by flow cytometry, the mRNA expression level of Foxp3 was quantified by RT-PCR, cytokine levels were measured by ELISA and CII-induced cell proliferation was quantified in vitro. Kirenol significantly delayed the occurrence and reduced the disease severity of CIA. Histological analysis confirmed Kirenol suppressed joint inflammation and inhibited cartilage and bone destruction, compared to the CIA group. Kirenol also upregulated the mRNA expression of Foxp3, increased the numbers of CD4⁺CD25⁺Foxp3⁺ and IL4⁺CD4⁺ T cells, and reduced the number of IFNγ⁺CD4⁺ T cells. Kirenol reduced the levels of TNF-α, IL-17A and IL-6 in synovial fluid and TNF-α, IL-17A and IFN-γ in serum, and increased the serum levels of IL-4, IL-10 and TGF-ß1. In addition, Kirenol inhibited the ability of CII to induce splenocyte, PBMC and lymph node cell proliferation in vitro, compared to cells from CIA rats. In conclusion, these results suggest that Kirenol may be a potential immunosuppressant for the treatment for rheumatoid arthritis.

Alkaptonuria.

A 69-year-old woman presented with a 30-year history of lower back and large joint pain of the hips and shoulders. On examination blue-grey, pigmented macules were present over the cartilaginous portions of the ears and on the sclera. Past medical history included aortic stenosis. Urine homogentisic acid level was elevated, which is diagnostic for alkaptonuria. Alkaptonuria is an autosomal recessive disorder that results in deficiency of homogentisic acid oxidase and in the accumulation of homogentisic acid in connective tissue. Disease can result in blue-grey pigmentation of the cartilage, sclerae, face, and hands as well as severe arthropathy and cardiac valve disease. Treatment is limited at this time. Promising early reports of the use of nitisinone have prompted ongoing trials of this therapeutic agent.

GATA-3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritis.

OBJECTIVE: Rheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon-gamma (IFNgamma)-producing Th1 cells or the novel T helper subset, interleukin-17 (IL-17)-producing Th17 cells, are the pathogenic mediators of joint inflammation in chronic nonautoimmune arthritis. Therefore, this study was aimed at examining whether the Th2-specific transcription factor GATA-3 can regulate arthritis, in an experimental murine model, by modulating Th1 and/or Th17 cell polarization. METHODS: Arthritis was induced with methylated bovine serum albumin (mBSA) in both wild-type and CD2 T cell-specific GATA-3 (CD2-GATA-3)-transgenic mice. At days 1 and 7 after the induction of arthritis, knee joints were scored macroscopically for arthritis severity and for histologic changes. Single-cell suspensions were generated from the spleens, lymph nodes, and inflamed knee joints. Cytokine expression by CD4+ T cells was determined using flow cytometry, and IL-17 expression in the inflamed knee joints was determined by enzyme-linked immunosorbent assay. Analyses of gene expression were performed for Th17-associated factors. RESULTS: Wild-type mice developed severe joint inflammation, including massive inflammatory cell infiltration and bone erosion that increased significantly over time, reaching maximal arthritis scores at day 7. In contrast, only mild joint inflammation was observed in CD2-GATA-3-transgenic mice. This mild effect was further accompanied by systemic and local reductions in the numbers of IL-17+IFNgamma- and IL-17+IFNgamma+, but not IL-17-IFNgamma+, CD4+ T cells, and by induction of Th2 cytokine expression. Moreover, GATA-3 overexpression resulted in reduced gene expression of the Th17-associated transcription factor retinoic acid-related orphan receptor gammat. CONCLUSION: These results indicate that enforced GATA-3 expression protects against severe joint inflammation and bone erosion in mice, accompanied by reduced differentiation of Th17 cells, but not Th1 cells, during mBSA-induced arthritis.

The role of chicken IL-1beta, IL-6 and TNF-alpha in the occurrence of amyloid arthropathy.

In this study, the roles of IL-1beta, IL-6 and TNF-alpha in amyloid arthropathic chickens with variable amounts (severe, moderate and mild) of amyloid accumulation were investigated. The presence and the levels of cytokines were evaluated in serum and in joint tissues by using ELISA and immunohistochemistry, respectively. One hundred brown layer chicks were allocated into four groups and intra-articular injections of Freund's adjuvant were used to induce amyloid arthropathy in Groups II, III and IV. Vitamin A in group II, and methylprednisolone in Group IV were added to enhance and to reduce the severity of amyloidosis, respectively. At the end of the study, a positive correlation was observed among the incidence and severity of amyloidosis, the serum amyloid A levels and the IL-1beta values both in the serum and tissues. Elevation in the tissue TNF-alpha levels in parallel with the severity of amyloidosis has also been noted. As a conclusion, IL-1beta appears to play an important role in avian AA amyloidosis either alone or in combination with TNF-alpha. Further investigation is needed for understanding the role of the pro-inflammatory cytokines in avian AA amyloidosis.

Cartilage-derived retinoic acid-sensitive protein in equine synovial fluid from healthy and diseased joints.

REASONS FOR PERFORMING STUDY: More sensitive and specific diagnostic methods for early detection of changes in the joint cartilage are needed. Cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a potential marker of cartilage synthesis and regeneration. This is the first study on equine CD-RAP. OBJECTIVES: To evaluate the ability of a commercially available human sandwich ELISA assay to detect equine CD-RAP in synovial fluid from healthy and diseased joints. METHODS: Synovial fluid was collected from 28 horses with no signs of joint disease and from 5 with induced inflammatory arthritis. CD-RAP concentrations were measured using a human CD-RAP ELISA. Intra- and interassay imprecision of the assay were evaluated by multiple measurements on pools of equine synovial fluid. Assay inaccuracy was determined by linearity under dilution. RESULTS: The assay showed moderate to large intra- and interassay variation when applied to equine synovial fluid. Equine CD-RAP was detected in synovial fluid from healthy horses ranged at 8.2-52 ng/ml. Repeated arthrocentesis (after injection of isotonic saline), age, joint or gender did not significantly affect CD-RAP concentrations. Twelve hours after intra-articular injection of lipopolysaccharide, concentrations of CD-RAP were significantly lower than after injection of isotonic saline and remained significantly lower until the end of the study at 144 h. CONCLUSION AND POTENTIAL RELEVANCE: The assay is suitable for longitudinal monitoring of CD-RAP concentration in individual horses. Disease significantly influenced CD-RAP levels. Similar to previous results obtained in man, CD-RAP seems to be a marker of cartilage synthesis and/or regeneration in horses.

[Paharmacological mechanisms of cellular immunity of overall alkali of tongbiling for the treatment of joint destruction].

AIM: To investigate the effect of the overall alkali of Traditional Chinese Medicine tongbiling(TBL) which comprises brucine and strychnine alkaloids on collagen induced-arthritis(CIA) and study its paharmacological mechanisms of cellular immunity. METHODS: Bovine CII was emulsified in Freund's incomplete adjuvant. Wistar rats were injected with Type II collagen intradermally at the base of the tail. After swelling, CIA groups were, randomly divided into physiological saline group and treatment group. Then the swelling of the rats' hindlimbs was evaluated. The whole body of the rats treated on 35 th days was photographed by mammography X-Ray. 96 joints in erosion scoring system and 100 joints in joint spacing narrow(JSN) scoring system were used to observe the joint destruction of CIA from X-Ray comprehensively and objectively. After the rats were killed, the third proximal claw pad of the right hindlimb and left forelimb were stained by HE dying, Neutrophil, lymphocyte, plasmacyte infiltration and hyperplasia of synoviocytes were assessed. Then MTT and Western blot were used to determine the effect of the overall alkali of TBL on proliferation of Jurkat cells and ERK1/2 phosphorylation of Jurkat cells, respectively. RESULTS: Inflammation of CIA joints was aggravated quickly. The swelling of CIA rats treated by MTX and overall alkali of TBL for 35 days was relieved (P<0.05). MTX and overall alkali of TBL inhibited the hyperplasia of synoviocytes. Overall alkali of TBL inhibited the infiltration of lymphocyteS and plasmacytes. Overall alkali of TBL inhibited the proliferation and ERK1/2 phosphorylation of Jurkat cells. CONCLUSION: Overall alkali of TBL could relieve joint inflammation and destruction of CIA rats by blocking the MAPK cell signalling pathway to inhibit the activation and proliferation of T cells. Our study might provide an experimental basis for treatment of rheumatoid arthritis with overall alkali of TBL.

[Beneficial effect of high-dose etidronate on periarticular calcinosis associated with arterial and periarticular basic calcium phosphate (BCP) crystal deposition disease].

Basic calcium phosphate (BCP) deposition disease is a crystal-induced inflammation syndrome. We report a beneficial effect of high-dose etidronate, one of the bisphosphonates, on periarticular calcinosis in a case of arterial and periarticular BCP crystal deposition disease. A 55-year-old woman was referred to St. Marianna University Hospital because of a 30-year history of recurrent acute periarthritis. The X-ray photographs revealed periarticular calcinosis of the hand and foot, wrist, and knee joints without bony erosions and the calcification of carotid and popliteal arteries. The biopsied specimen from periarticular tissue showed Alizalin-red and von Kossa staining-positive crystals. With the diagnosis of BCP crystal-induced periarthritis, she has been treated with colchicine and probenecid. This regimen was partially effective in terms of a decrease in the frequency of periarthritic attack. Despite the treatment, periarticular calcinosis increased in size and number. She was treated with 800 mg of etidronate 3 months after the etidronate therapy; periarticular calcinosis was diminished although arterial calcification was unchanged. This case suggests that high-dose etidronate might be useful for heterotopic calcification associated with rheumatic diseases.

Adenoviral gene transfer of interleukin-1 in combination with oncostatin M induces significant joint damage in a murine model.

Oncostatin M (OSM) is an interleukin (IL)-6 family cytokine that we have previously shown can synergize with a number of proinflammatory cytokines to promote the release of collagen from cartilage in explant culture. However, the effects of this potent cytokine combination in vivo are not known. Using adenoviral gene transfer, we have overexpressed murine IL-1 (AdmIL-1) and murine OSM (AdmOSM) intraarticularly in the knees of C57BL/6 mice. Histological analyses indicated marked synovial hyperplasia and inflammatory cell infiltration for both AdmIL-1 and AdmOSM but not in control joints. This inflammation was even more pronounced for the AdmIL-1+AdmOSM combination with evidence of cartilage and bone destruction. Significant loss of both proteoglycan and collagen was also seen for this combination, and immunohistochemistry revealed an increased expression of matrix metalloproteinases (MMPs) with decreased tissue inhibitor of metalloproteinases (TIMPs) in both articular cartilage and synovium. Similar expression profiles for MMPs/TIMPs were found in IL-1+OSM-stimulated human articular chondrocytes. Taken together, these data confirm that, in vivo, OSM can exacerbate the effects of IL-1 resulting in inflammation and tissue destruction characteristic of that seen in rheumatoid arthritis. We provide further evidence to implicate the up-regulation of MMPs as a key factor in joint pathology.

Excitatory amino acid profiles of synovial fluid from patients with arthritis.

OBJECTIVE: Previous studies in an experimental synovitis model in rats determined that administration of glutamate and aspartate into the joint produces hyperalgesic responses, while their receptor antagonists provide protection against the development of a hyperalgesic state. We examined concentrations of amino acids in synovial fluid (SF) to determine if increases might be relevant to human joint pathology. METHODS: One hundred forty-four repository SF samples from patients undergoing diagnostic or therapeutic arthrocentesis and 14 SF samples from 7 cadavers were analyzed by high pressure liquid chromatography and compared as arthritic and control cohorts. RESULTS: Compared to the average concentrations from the autopsy cases, the excitatory amino acids (EAA) glutamate and aspartate in SF from patients with synovitis were 54 and 28 times higher, respectively. Increases for all other amino acids ranged from 3 to 18-fold. The values for glutamate and aspartate were significantly higher than the mean increase for other amino acids compared using unpaired t tests (p < 0.0001). The mean ratio of glutamate and aspartate elevations over the mean increase for other amino acids was 4-fold and 2-fold, respectively. The EAA were highest in Reiter's, infectious arthropathies, and systemic lupus erythematosus, but did not appreciably segregate to diagnosis or SF white blood cell count. CONCLUSION: Our data provide evidence of increased glutamate and aspartate in the SF of humans with active arthritis, suggesting that glutamate mediated events may contribute to the pathogenesis of human arthritic conditions.