Rheumatoid Arthritis: Huang H

Tu G, Xu W, Huang H, Li S. · Department of Medicinal Chemistry, School of Pharmaceutical Sciences, ShanDong University, 44, West Culture Road, Ji'nan, 250012, P.R. China. · Curr Med Chem. · Pubmed #18537616 No free full text.

Abstract: Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.Thus, MMP inhibitors (MMPIs) are expected to be useful for the treatment of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. A vast number of MMPIs have been developed in recent years.With the failure of these inhibitors in clinical trials,more efforts have been directed to the design of specific inhibitors with different Zn-binding groups. This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs , a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMPIs, and a clinical update of compounds that have entered clinical trials in humans.

Huang H, Hutta DA, Rinker JM, Hu H, Parsons WH, Schubert C, DesJarlais RL, Crysler CS, Chaikin MA, Donatelli RR, Chen Y, Cheng D, Zhou Z, Yurkow E, Manthey CL, Player MR. · Johnson & Johnson Pharmaceutical Research and Development, Welsh and McKean Roads, Spring House, Pennsylvania 19477-0776, USA. · J Med Chem. · Pubmed #19193011 No free full text.

Abstract: A series of pyrido[2,3-d]pyrimidin-5-ones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). FMS inhibitors may be useful in treating rheumatoid arthritis and other chronic inflammatory diseases. Structure-based optimization of the lead amide analogue 10 led to hydroxamate analogue 37, which possessed excellent potency and an improved pharmacokinetic profile. During the chronic phase of streptococcal cell wall-induced arthritis in rats, compound 37 (10, 3, and 1 mg/kg) was highly effective at reversing established joint swelling. In an adjuvant-induced arthritis model in rats, 37 prevented joint swelling partially at 10 mg/kg. In this model, osteoclastogenesis and bone erosion were prevented by low doses (1 or 0.33 mg/kg) that had minimal impact on inflammation. These data underscore the potential of FMS inhibitors to prevent erosions and reduce symptoms in rheumatoid arthritis.

Monach P, Hattori K, Huang H, Hyatt E, Morse J, Nguyen L, Ortiz-Lopez A, Wu HJ, Mathis D, Benoist C. · Section of Immunology and Immunogenetics, Joslin Diabetes Center, Boston, MA, USA. · Methods Mol Med. · Pubmed #17983155 No free full text.

Abstract: Mice expressing the KRN T cell receptor transgene and the MHC class II molecule A(g7) (K/BxN mice) develop severe inflammatory arthritis, and serum from these mice causes similar arthritis in a wide range of mouse strains, owing to pathogenic autoantibodies to glucose-6-phosphate isomerase (GPI). This model has been useful for the investigation of the development of autoimmunity (K/BxN transgenic mice) and particularly of the mechanisms by which anti-GPI autoantibodies induce joint-specific imflammation (serum transfer model). In this chaper, after a summary of findings from this model system, we describe detailed methods for the maintenance of a K/BxN colony, crossing of the relevant TCR and MHC genes to other strain backgrounds, evaluation of KRN transgenic T cells, measurement of anti-GPI antibodies, induction of arthritis by serum transfer, and clinical and histological evaluation of arthritis.

Han C, Huang H, Hu M, Wang Q, Gao Y, Liu Y. · Department of Pharmacology and Toxicology, Beijing Institute of Radiation Medicine, Beijing 100850, China. · Prostaglandins Other Lipid Mediat. · Pubmed #17481560 No free full text.

Abstract: Leukotriene B4 acts through its receptors, BLT(1) and BLT(2), however, their expression in rheumatoid arthritis is unknown. In this experiment, BLT(1) and BLT(2) mRNA expressions in the synovium of rats with collagen-induced arthritis (CIA) at days 1, 3, 7 and 14 after CIA onset were analyzed by RT-PCR. The expression of two immunological and inflammatory factors, S100A8 and S100A9, in the synovium of the arthritic rats was also determined at the indicated time. At d14, the differential expressions of BLT(1) and BLT(2) in the synovium, spleen, peripheral blood mononuclear cells (PBMC) and thymus of CIA rats were analyzed. The results showed that, in the synovium of the arthritic rats, the BLT(1) mRNA expression increased after CIA onset, reached the highest value between d1 and d3, and declined afterwards while the BLT(2) expression increased with time and reached its peak at d14. Both S100A8 and S100A9 expression reached the peak levels between d1 and d3, and decreased to lower levels between d7 and d14. For the analyzed tissues from CIA rats at d14, BLT(1) mRNA was expressed in the thymus with the highest level, followed by the spleen, PBMC and synovium. BLT(2) mRNA was expressed in the thymus the highest as well, but followed by the synovium, spleen and PBMC. Since BLT(1) and BLT(2) play distinct roles during CIA, this study may provide basis for new therapies targeting BLT(1) and BLT(2), respectively, for the treatment of arthritic inflammation at different stages.

Liu M, Wang X, Yin C, Zhang Z, Lin Q, Zhen Y, Huang H. · Faculty of Life Science, Hubei University, 430062 Wuhan, People's Republic of China. · Biochem J. · Pubmed #17472572 links to  free full text

Abstract: Anti-TNF-alpha [anti-(tumour necrosis factor-alpha)] therapy is widely considered to be among the most efficient treatments available for rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. In the present study a tetravalent mini-antibody, named 'TNF-TeAb', was constructed by fusing the tetramerization domain of human p53 to the C-terminus of an anti-TNF-scFv [anti-(TNF-alpha-single-chain variable fragment)] via a long and flexible linking peptide derived from human serum albumin. TNF-TeAb was overexpressed as inclusion bodies in the cytoplasm of Escherichia coli, purified to homogeneity by immobilized- metal affinity chromtaography under denaturing conditions and produced in functional form by using an in vitro refolding system. In vitro bioactivity assays suggested that tetramerization of TNF-scFv resulted in an enormous gain in avidity, which endowed TNF-TeAb with a stronger ability to inhibit both receptor binding and cytolytic activity of TNF-alpha. TNF-alpha targeting therapy in rats with collagen-induced arthritis demonstrated that TNF-TeAb provided a much more significant therapeutic effect than did TNF-scFv in suppressing arthritis progression, attenuating inflammation and destruction in joints, and down-regulating pro-inflammatory cytokines and anti-(type II collagen) antibody. The conclusions are therefore (i) that multimerization of the antibody fragment by a self-association peptide is an efficient way to increase its avidity and (ii) that TNF-TeAb has potential applicability for anti-TNF-alpha therapy.

Gui JC, Wang LM, Zhang HW, Huang H, Fang YG, Liu LF, Fan SH, Gu XJ, Wang X. · Department of Orthopaedics, Nanjing First Hospital, Nanjing Medical University, Nanjing 210006, China. Email: · Zhonghua Wai Ke Za Zhi. · Pubmed #17081465 No free full text.

Abstract: OBJECTIVE: To investigate the method and result of arthroscopic trans-septal approach (ATS). METHODS: Ten fresh cadaveric knees were prepared for anatomical study about the posterior septum, and 65 posterior compartment arthroscopy of the knees were performed to view the structure of the posterior septum. The initial diagnosis included: rheumatoid arthritis, pigmented villonodular synovitis, osteoarthritis, loose body or foreign body in the posterior compartment, posterior cruciate ligament (PCL) injury or avulsion fracture, posterior horn tear of meniscus, undiagnosed swollen knee with pain and effusion, osteochondritis dissecans, pyogenic arthritis, gout. From January 2002 to June 2005, 22 cases of ATS were applied. Anterolateral portal was initially created, followed by posterolateral portal under the viewing of arthroscopy which was located at the anterolateral portal. Anteromedial and posteromedial portals were also created using the same technique. Arthroscopy was then transferred to the posteromedial portal, and blade was introduced from the anteromedial portal to gradually remove the synovium covering PCL. Arthroscopy was relocated to the anteromedial portal, Wissinger rod was introduced from the posteromedial portal and pointed to the posterior septum adjacent to the posterior edge of the midportion of PCL. The Wissinger rod was pushed carefully to pierce through the posterior septum under the sight of arthroscopy which was located at the posterolateral portal. ATS was finally created. RESULTS: The posterior septum was in the middle of posterior compartment of the knee, which was film screen-like at the sagittal plane and sandwich-like at the transverse plane. The synovium covered the posterior septum at arthroscopic inspection. Twenty-two cases of ATS were successfully created, amounting to 34% (22/65) of all cases at the same period which had received the arthroscopy of posterior compartments of the knees. Synovectomy of the posterior compartments of the knees was performed in 7 cases, loose body removal was in 6 cases, PCL reconstruction was in 4 cases, reduction and fixation of PCL avulsion fracture was in 2 cases. Chondroplasty, inflammatory synovectomy, and meniscectomy were performed accordingly in 6 osteoarthritis cases. No vascular or nervous injury was encountered. At an average of 20 months follow-up (range, 4 to 45 months), 9 cases still had mild knee pain or swelling, 2 cases had severe pain and were recommended for total knee replacement, the other 11 cases had no recurrence of knee pain or swelling. CONCLUSIONS: ATS has no blind area under arthroscopic vision and facilitate trans-septal operation. It is a safe and effective method to treat the diseases of the posterior compartment of the knee. The direction of inside to outside to create ATS is comparatively reliable, and PCL could be identified as an interior landmark during the passage of Wissinger rod through posterior septum to create ATS.

Maccioni M, Zeder-Lutz G, Huang H, Ebel C, Gerber P, Hergueux J, Marchal P, Duchatelle V, Degott C, van Regenmortel M, Benoist C, Mathis D. · Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), 67000 Strasbourg, France. · J Exp Med. · Pubmed #11956298 links to  free full text

Abstract: Arthritis in the K/BxN mouse model is provoked by pathogenic antibodies (Abs) directed against a ubiquitously expressed protein, glucose-6-phosphate isomerase (GPI). To begin dissecting the repertoire of arthritogenic immunoglobulins (Igs) in the K/BxN model, and to provide a basis for comparison with RA patients we have generated anti-GPI monoclonal Abs (mAbs) from spontaneously activated B cells in the lymphoid organs of arthritic mice. B cell clones with anti-GPI specificities were present at extraordinarily high frequencies in the spleen, and less frequently in other lymphoid organs and in the synovial fluid. None of the anti-GPI mAbs induced arthritis when injected individually into healthy recipients, but most were effective when combined in pairs or larger pools. Arthritogenic combinations depended on mAbs of the IgG1 isotype, which bound to GPI with Kd in the 10(-9) M range, with no indication of cooperative binding between complementing pairs. Pathogenicity was not associated with recognition of a particular epitope, but the ability to form mAb/GPI multimers by simultaneous recognition of different epitopes was clearly required, consistent with the known role of complement and FcRs in this model. Sequence analysis revealed structural similarities amongst the mAbs, indicating that a particular subset of B cells may evade tolerance in K/BxN mice, and that affinity maturation by somatic mutation likely takes place. These results confirm that GPI itself, rather than a cross-reactive molecule, is the target of pathogenic Igs.

Wang SJ, Lin WY, Chen MN, Chen JT, Ho WL, Hsieh BT, Huang H, Shen LH, Ting G, Knapp FF. · Department of Nuclear Medicine, Veterans General Hospital, Taichung and National Yang-Ming University, 160 Taichung Harbor Road, Section 3, 40705, Taichung, Taiwan. · Nucl Med Biol. · Pubmed #11518655 No free full text.

Abstract: Rhenium-188 microsphere is a relatively new radiation synovectomy agent developed for the treatment of rheumatoid arthritis. It has been shown that the levels of unwanted extra-articular radiation are negligible with this agent. A histologic study was conducted to assess the effect of radiation synovectomy on synovium and articular cartilage after intra-articular injection of various doses of Re-188 microspheres into the knee joints of rabbits. Intra-articular injection of Re-188 microspheres into rabbit knee joints resulted in mild reactive inflammation and thrombotic occlusion of vessels which subsided rapidly. Sclerosis of subsynovium could be seen 12 weeks after injection. No evidence of damage to articular cartilage was noted. There was no significant difference in the articular pattern after injection of 0.3 or 0.6 mCi Re-188 microspheres. This study suggests that a treatment dose of Re-188 microspheres causes transient inflammation of synovium without any detectable damage to the articular cartilage of knee joint.