Outcome of unlinked total elbow arthroplasty for rheumatoid arthritis in patients younger than 50 years old.

AIMS: There are concerns regarding complications and longevity of total elbow arthroplasty (TEA) in young patients, and the few previous publications are mainly limited to reports on linked elbow devices. We investigated the clinical outcome of unlinked TEA for patients aged less than 50 years with rheumatoid arthritis (RA). METHODS: We retrospectively reviewed the records of 26 elbows of 21 patients with RA who were aged less than 50 years who underwent primary TEA with an unlinked elbow prosthesis. The mean patient age was 46 years (35 to 49), and the mean follow-up period was 13.6 years (6 to 27). Outcome measures included pain, range of motion, Mayo Elbow Performance Score (MEPS), radiological evaluation for radiolucent line and loosening, complications, and revision surgery with or without implant removal. RESULTS: The mean MEPS significantly improved from 47 (15 to 70) points preoperatively to 95 (70 to 100) points at final follow-up (p < 0.001). Complications were noted in six elbows (23%) in six patients, and of these, four with an ulnar neuropathy and one elbow with postoperative traumatic fracture required additional surgeries. There was no revision with implant removal, and there was no radiological evidence of loosening around the components. With any revision surgery as the endpoint, the survival rates up to 25 years were 78.1% (95% confidence interval 52.8 to 90.6) as determined by Kaplan-Meier analysis. CONCLUSION: The clinical outcome of primary unlinked TEA for young patients with RA was satisfactory and comparable with that for elderly patients. A favourable survival rate without implant removal might support the use of unlinked devices for young patients with this disease entity, with a caution of a relatively high complication rate regarding ulnar neuropathy.Level of Evidence: Therapeutic Level IVCite this article: Bone Jt Open 2023;4(1):19-26.

Minoxidil Cannot Be Used To Target Lysyl Hydroxylases during Postnatal Mouse Lung Development: A Cautionary Note.

The lysyl hydroxylases (procollagen-lysine 5-dioxygenases) PLOD1, PLOD2, and PLOD3 have been proposed as pathogenic mediators of stunted lung development in bronchopulmonary dysplasia (BPD), a common complication of preterm birth. In affected infants, pulmonary oxygen toxicity stunts lung development. Mice lacking Plod1 exhibit 15% mortality, and mice lacking Plod2 or Plod3 exhibit embryonic lethality. Therefore, to address any pathogenic role of lysyl hydroxylases in stunted lung development associated with BPD, minoxidil was administered to newborn mice in an oxygen toxicity-based BPD animal model. Minoxidil, which has attracted much interest in the management of systemic hypertension and androgenetic alopecia, can also be used to reduce lysyl hydroxylase activity in cultured cells. An in vivo pilot dosing study established 50 mg⋅kg-1⋅day-1 as the maximum possible minoxidil dose for intraperitoneal administration in newborn mouse pups. When administered at 50 mg⋅kg-1⋅day-1 to newborn mouse pups, minoxidil was detected in the lungs but did not impact lysine hydroxylation, collagen crosslinking, or lysyl hydroxylase expression in the lungs. Consistent with no impact on mouse lung extracellular matrix structures, minoxidil administration did not alter the course of normal or stunted lung development in newborn mice. At doses of up to 50 mg⋅kg⋅day-1, pharmacologically active concentrations of minoxidil were not achieved in neonatal mouse lung tissue; thus, minoxidil cannot be used to attenuate lysyl hydroxylase expression or activity during mouse lung development. These data also highlight the need for new and specific lysyl hydroxylase inhibitors. SIGNIFICANCE STATEMENT: Extracellular matrix crosslinking is mediated by lysyl hydroxylases, which generate hydroxylated lysyl residues in procollagen peptides. Deregulated collagen crosslinking is a pathogenic component of a spectrum of diseases, and thus, there is interest in validating lysyl hydroxylases as pathogenic mediators of disease and potential "druggable" targets. Minoxidil, administered at the maximum possible dose, did not inhibit lysyl hydroxylation in newborn mouse lungs, suggesting that minoxidil was unlikely to be of use in studies that pharmacologically target lysyl hydroxylation in vivo.

Results of Total Elbow Arthroplasty with Cementless Implantation of an Alumina Ceramic Elbow Prosthesis for Patients with Rheumatoid Arthritis.

We investigated the long-term clinical results of total elbow arthroplasty (TEA) by cementless fixation of alumina ceramic unlinked elbow prostheses (J-alumina ceramic elbows: JACE) for the reconstruction of elbow joints with rheumatoid arthritis (RA). Seventeen elbows in 17 patients (aged 44-72 years, average 54.8) replaced by JACE TEA without bone cement were investigated. The average follow-up period was 10.7 (range, 1.0-19.3) years. Clinical conditions of each elbow before and after surgery were assessed according to the Mayo Elbow Performance Index (MEPI). Radiographic loosening was defined as a progressive radiolucent line of more than 1 mm that was completely circumferential around the intramedullary stem. The average MEPI significantly improved from 46.8 points preoperatively to 66.8 points at final follow-up (p=0.0226). However, aseptic loosening was noted in 10 of 17 elbows (58.8%) and revision surgery was required in 7 (41.2%). Most loosening was observed on the humeral side. With radiographic loosening and revision surgery defined as the end points, the likelihoods of prosthesis survival were 41.2% and 51.8%, respectively, up to 15 years by Kaplan-Meier analysis. The clinical results of JACE implantation without bone cement were disappointing, with high revision and loosening rates of the humeral component.

Short-term results of the PROSNAP linked elbow prosthesis with a snap-in structure and modular flange for the reconstruction of severely damaged rheumatoid elbows.

BACKGROUND: We aimed to evaluate the early clinical results of the reconstruction of problematic elbow joints due to rheumatoid arthritis (RA) using a PROSNAP linked elbow prosthesis (Kyocera Medical, Osaka, Japan) for total elbow arthroplasty. METHODS: Seventeen elbows in 14 RA patients were replaced with a PROSNAP elbow with cement fixation. The patients comprised 1 man and 13 women, with a mean age of 63.9 years (range, 52-83 years) at the time of surgery. The preoperative conditions of the elbows were arthritis mutilans (n = 10), an ankylosed or stiff elbow with a preoperative range of motion of 45° or less (n = 4), and loosening of a primary total elbow arthroplasty (n = 3). The mean follow-up period was 47.7 months (range, 32-69 months), with a 100% follow-up rate. The clinical outcome of the elbows was evaluated by the Mayo Elbow Performance Index (maximum, 100 points). RESULTS: The mean postoperative Mayo Elbow Performance Index score improved from 57.6 points to 97.1 points. Preoperatively, 3 of the 17 elbows were judged as good, 7 as fair, and 7 as poor; at final follow-up, 16 elbows were judged as excellent and 1 as good. Complications were noted in 1 elbow (6%), which had undergone a postoperative fracture. CONCLUSIONS: The PROSNAP elbow prosthesis can be safely implanted through a relatively easy procedure and provides satisfactory short-term clinical outcomes for the reconstruction of severely damaged RA elbows. LEVEL OF EVIDENCE: Level IV, case series, treatment study.

Japanese Cancer Association Meeting UICC International session--what is cost-effectiveness in cancer treatment?

The Japan National Committee for the Union for International Cancer Control (UICC) and UICC-Asia Regional Office (ARO) organized an international session as part of the official program of the 72nd Annual Meeting of the Japanese Cancer Association to discuss the topic "What is cost-effectiveness in cancer treatment? " Healthcare economics are an international concern and a key issue for the UICC. The presenters and participants discussed the question of how limited medical resources can be best used to support life, which is a question that applies to both developing and industrialized countries, given that cancer treatment is putting medical systems under increasing strain. The emergence of advanced yet hugely expensive drugs has prompted discussion on methodologies for Health Technology Assessment (HTA) that seek to quantify cost and effect. The session benefited from the participation of various stakeholders, including representatives of industry, government and academia and three speakers from the Republic of Korea, an Asian country where discussion on HTA methodologies is already advanced. In addition, the session was joined by a representative of National Institute for Health and Care Excellence (NICE) of the United Kingdom, which has pioneered the concept of cost-effectiveness in a medical context. The aim of the session was to advance and deepen understanding of the issue of cost-effectiveness as viewed from medical care systems in different regions.

A 5-22-year follow-up study of stemmed alumina ceramic total elbow arthroplasties with cement fixation for patients with rheumatoid arthritis.

BACKGROUND: We determined mid to long-term results of total elbow arthroplasty (TEA) by use of unlinked elbow prostheses with solid alumina ceramic trochleae, and ceramic ulnar stems (stemmed Kyocera type I; SKC-I) for patients with rheumatoid arthritis. PATIENTS AND METHODS: Fifty-four elbows of 39 patients were available for detailed clinical and radiographic review after a follow-up period of at least 5 years. The mean follow-up period was 12.6 years (range 5-22 years). Clinical condition before and after surgery was assessed by use of a modified version of the Mayo Elbow Performance Score (MEPS; 0-100 points) and a Japan Orthopaedic Association Elbow score (JOA score; 0-100 points). The radiographs were reviewed and loosening was defined as a progressive radiolucent line >1 mm wide that was completely circumferential around the prosthesis. Clinical records of post-operative events affecting the elbows were used for survival analysis of the prostheses using the Kaplan-Meier method. RESULTS: The average modified MEPS and JOA scores improved significantly from 39.7 ± 14.3 to 44.7 ± 9.4, respectively, pre-operatively, to 89.7 ± 15.4 and 83.1 ± 12.8, respectively, post-operatively (P < 0.0001). The functional assessment score also improved from 4.9 ± 2.8 to 8.5 ± 3.3 points (P < 0.0001). With loosening or implant revision defined as end points, the likelihood of survival of the prosthesis for up to 20 years was 92.6% (95% confidence interval (CI), 85.6-100.0) or 86.3 % (95 % CI 75.0-97.6), respectively. CONCLUSION: Satisfactory clinical results were obtained after TEA using SKC-I prostheses, which provided excellent pain relief and functional range of motion. The results of our study reveal the high reliability over a long period of the cemented SKC-I prosthesis with an alumina ceramic component.

The clock gene brain and muscle Arnt-like protein-1 (BMAL1) is involved in hair growth.

It is known that baldness caused by androgenetic alopecia is involved with androgen and the androgen receptor. Furthermore, it has been reported that testosterone secretion follows a circadian rhythm. Therefore, we hypothesized that a relationship exists between androgen-induced alopecia and biological rhythm. The mammalian circadian rhythm is controlled by several clock genes. Brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1), one of the clock genes, is a transcription factor that plays central roles in the regulation of circadian rhythms. In this study, we investigated the influence of BMAL1 on hair follicle functions and hair growth. Mice deficient in BMAL1 expression exhibited a delay in hair regrowth after shaving. In hair follicles of mouse vibrissa, expression of Bmal1 and other clock genes was found to be rhythmic. Knockdown of BMAL1 in human follicle dermal papilla cells resulted in modulation of expression of several hair growth-related genes. Therefore, we concluded that expression of clock genes in hair follicles is linked to the circadian rhythm and that BMAL1 can regulate hair growth.

Specific enhancement of vascular endothelial growth factor (VEGF) production in ischemic region by alprostadil--potential therapeutic application in pharmaceutical regenerative medicine.

Alprostadil (lipo-PGE1) is a drug delivery system preparation. This preparation is applied to treat refractory skin ulcers and arteriosclerosis obliterans. We investigated the effects of alprostadil by using the earflap ischemic model. The following results were obtained: 1) Treatment with alprostadil significantly increased the VEGF contents in an ischemic ear; 2) Treatment with alprostadil resulted in strongly expressed VEGF levels only in the ischemic region; 3) Image analysis revealed a significant increase in the number of vessel bypasses and paths after flap creation with alprostadil administration compared to the vehicle-treated ears. The results suggest that it may be possible to apply alprostadil as one device for regenerative medical technology.

The eighth Asia cancer forum: seeking to advance the outcomes of the UN summit: 'global health as the key to a new paradigm in cancer research'.

To date, the Asia Cancer Forum has focused its efforts on creating a common concept for collaborative efforts in international cancer research with a focus on Asia, where cancer incidence is rising dramatically, and also sharing information and knowledge among cancer specialists about the importance of cancer as a global health agenda issue. The Eighth Asia Cancer Forum was held following the historic outcome of the High-level Meeting of the United Nations General Assembly on the Prevention and Control of Non-communicable Diseases held in New York in September 2011, at which cancer was duly recognized as a global health agenda issue. Despite this significant development, however, the issue of cancer, one of the most intractable of all non-communicable diseases, still faces a variety of challenges if it is to be addressed on the global level. The Eighth Asia Cancer Forum sought to address these various issues, seeking ways to capitalize on the outcomes of the UN Meeting and take global collaborative studies and alliances in the field of cancer further. It was recognized that one of the main challenges for the Asia Cancer Forum is to formulate a proposal that demonstrates how middle-income countries can provide a good level of care using only their own limited medical resources. Given that the Asia Cancer Forum is one of the organizations that can provide assistance in working to further boost awareness about cancer research and the situation relating to cancer in Asian countries, discussion also focused on how to concretize activities in the future.

The 7th Asia Cancer Forum: from the perspective of human security, how can we collaborate as Asians in order to place cancer on the global health agenda? How can we fill in the gaps that exist among us?

This forum has continued to discuss the inclusion of cancer on the global health agenda, and specifically the Millennium Development Goals. The seventh forum presented an overview of activities to date, supplemented by reports from Korea, local governments in Japan and representatives from the pharmaceutical industry. Discussion focused on how to engage in measures to tackle cancer prevention and achieve early detection and effective treatment, using limited resources. It was recognized that with non-communicable diseases gaining increasing attention in international dialogue, it is now of the utmost importance to share an accurate recognition of cancer research and treatment throughout Asia and the wider world. Participants concurred that cancer issues are decoupled from the development aid agenda and that cooperation should be advanced on the basis of international cooperation without recourse to governmental development aid.

Comparison of bioabsorbable materials for use in artificial tracheal grafts.

Limited information exists regarding the usefulness of bioabsorbable materials in the design of tracheal grafts. The aim of this study was to evaluate the feasibility of three bioabsorbable materials for use as artificial trachea. Three sets of grafts were prepared: Group 1 (n=6), knitted polyglactin 910 mesh; Group 2 (n=3), copolymer of L-lactide and epsilon-caprolactone sponge reinforced with polyglycoride fibers; and Group 3 (n=8), copolymer of L-lactide and epsilon-caprolactone sponge covered with knitted poly-L-lactide mesh. All grafts were internally reinforced with a titanium stent. A 10-cartilage-ring-length of canine mediastinal trachea was resected and replaced by a bioabsorbable prosthesis with the aid of an omental flap. In Groups 1 and 2, the patency rates decreased below 50% within two months after surgery. In Group 3, six of eight dogs maintained patency rates above 50% from 10 months to 2 years after surgery. Grafts prepared with a copolymer of L-lactide and epsilon-caprolactone sponge covered with knitted poly-l-lactide mesh (Group 3) can function for up to two years after surgery. These results provide evidence toward the feasibility of utilizing bioabsorbable materials as a tracheal prosthesis.

Re-epithelialization after laser therapy of a stenotic artificial tracheal graft: a pilot experimental study.

Tracheal reconstruction is a challenging field of research for thoracic surgeons. Recent tracheal grafting studies report short observation times, which make it difficult to conclusively evaluate efficacy. Long-term studies examining the durability of artificial trachea strategies are needed. An ideal artificial trachea strategy would allow for no intervention following replacement, but this approach is presently infeasible. Today, interventional bronchoscopic techniques are widely accepted as a follow-up to airway problems after surgery. Our laboratory developed a semiconductor laser method for endobronchial treatment of stenotic implanted artificial trachea grafts. We herein report the results of a pilot study testing the endobronchial laser treatment in a canine model. The laser treatment yielded vigorous airway re-epithelialization on the graft from the native trachea.

Application for regenerative medicine of epithelial cell culture-vistas of cultured epithelium.

This review describes culture techniques for the epithelial system as well as trends in the clinical application of cultured keratinocytes in our department and the possibility of applying the techniques to other organs. Cultured epithelium and cultured dermis in particular have considerably preceded regeneration of other organs in the field of regenerative medicine. Since 1988 we have grafted cultured keratinocytes by the Rheinwald-Green modified method in at least 500 patients with large skin defects. As a result of the establishment of a culture technique for individual patients, it is now possible to prepare enough regenerated epithelium to cover the body surface area of as many as 10 adult patients in approximately three weeks after collecting 1 cm(2) of skin, and then remaining cultured keratinocytes can be cryo-preserved for two-stage dermatoplasty at another site. This procedure makes it possible to avoid frequent skin collection from the same patient and thereby improves patients' quality of life and activities of daily living. On the other hand, to solve the problem of regenerated epithelium shrinking and problems with graft efficiency on dermis defect lesion, we have developed a proteinase-resistant regenerated dermis by mixing a certain protein with a fibrin scaffold. Recently we also took the initiative in grafting hybrid-type regenerated trachea in an animal experiment by using the epithelial and dermal cell culture technique, and some results of the graft were obtained.

Custom AO small T plate for transcondylar fractures of the distal humerus in the elderly.

The purpose of this study was to present a new internal fixation technique for transcondylar fractures of the humerus in elderly patients. Seventeen patients, aged older than 70 years, with displaced transcondylar fractures were treated by our new surgical method. All fractures were fixed by a customized AO small T plate and a transcondylar screw passed from the lateral epicondyle to the medial wall of the trochlea across the humeral condyle. The plate was hand-shaped, trimmed, and applied at the lateral side of the fracture site, and either a cannulated cancellous screw or an AO one-third tubular plate was applied at the medial side of the fracture site. All patients in this study had osteoporotic bone and a small distal fragment. They were followed up for a mean of 30 months (range, 24 to 60 months). Radiographically, union was achieved completely in all patients, and all except 1 had maintained the postoperative alignment. Bone graft or cement fixation was not required in any case. The assessment of the results by use of the modified Cassebaum's rating scale was excellent in 3 cases, good in 11, and fair in 3. With the custom AO small T plate and transcondylar screw fixation technique, the screw that passes through the humeral condyle provides good stability even in cases with a small osteoporotic fragment of the distal humerus. The screw does not damage the articular surface of the elbow joint, and stable fixation can be obtained even in osteoporotic bone.

Accuracy of a portable electroneurometer for measuring distal motor latency.

BACKGROUND: A facile electromyographic test in the outpatient clinic is needed to evaluate the outcome of screening for carpal tunnel syndrome. The purpose of the current prospective study was to compare the accuracy of Nervepace digital electroneurometer (Nervepace) and Dantec Neuromatic 2000M (Dantec) measurements of a wide range of distal motor latency (DML) of the median nerve. METHODS: The DML values for 112 of 126 median nerves examined with Nervepace and conventional electromyography, Dantec were statistically analyzed in this prospective study. The 30 hands of 15 clinically healthy adults 20-24 years old served as the reference group. Sixty consecutive patients (96 hands) with idiopathic carpal tunnel syndrome provided a wider range of DML values. All of the patients had standard clinical tests and standard motor (Dantec and Nervepace) and sensory (Dantec) electrodiagostic tests before endoscopic carpal tunnel release. RESULTS: The DML was measurable in all 30 hands of the reference group, in all 96 hands of the patients by Dantec, but in only 82 hands (52 patients) by Nervepace. Nervepace and Dantec DML values of 6.0 ms or less had high correlation and agreement. CONCLUSIONS: Correlation and agreement decreased significantly among values greater than 6.0 ms.

Effect of vision on postural sway in anterior cruciate ligament injured knees.

Recent clinical studies have investigated postural sway characteristics in anterior cruciate ligament (ACL)-deficient knees, but the relative contributions of vision and ACL remain unclear. In the current study, we measured and compared postural sway during one-leg standing with eyes open and closed to assess the difference between legs with and without ACL injury, and we discuss the contribution of the ligament relative to vision and to postural sway in patients. We examined 32 patients (17 males, 15 females) with ACL injury before surgery from March 2001 through January 2004. None presented obvious dysfunction in the lower limbs or central nervous system. Using a gravicorder, we measured locus length per time (LG) and environmental area (AR) as the factors of postural sway during two-leg and one-leg standing with eyes open or closed. In the ACL-injured knee, the amount of postural sway increased significantly during injured leg standing with eyes closed (LG, P < 0.0001; AR, P < 0.0001), but it did not increase significantly with eyes open. There were no significant differences with respect to sex or general joint laxity. There was no correlation between postural sway and the anterior translation of the tibia measured by arthrometer KT2000 or between the muscle strength around the knee. We concluded that the amount of postural sway in the ACL-injured knee increased significantly on injured leg standing with eyes closed, and that vision appears to be dominant in compensating for the decreased contribution of the injured ACL.

Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo.

About 97% of synovial sarcomas harbor the SYT-SSX fusion gene by chromosomal translocation. We found that the histone deacetylase (HDAC) inhibitor FK228 significantly suppressed the growth of synovial sarcoma cells as compared with that of osteosarcoma. The 50% growth inhibition IC50 value we obtained for FK228 was 0.02-0.2 nM, and it indicates that its suppression effect on synovial sarcoma cells is the highest of any of the HDAC inhibitors yet reported. It was not likely that the growth suppression of FK228 depends on the doubling time of these cells. Introduction of SYT-SSX cDNA into HEK293 cells enhanced the sensitivity of the cells for FK228. Immunostaining of the FK228-treated cells using an anti-acetyl-histone H3 antibody showed that FK228 inhibits deacetylation of histone. In a mice assay, the growth of synovial sarcoma cells was markedly inhibited by FK228 treatment, and the invasion of tumors into surrounding tissues was suppressed. These results suggest that FK228 may be useful in developing therapeutic strategies to treat synovial sarcoma.

Suppression of chondrosarcoma cells by 15-deoxy-Delta 12,14-prostaglandin J2 is associated with altered expression of Bax/Bcl-xL and p21.

We previously reported that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), the most potent agonist for peroxisome proliferator-activated receptor gamma (PPAR gamma), induces apoptosis of human chondrosarcoma cell line OUMS-27. The current study aimed to explore the mechanism of 15d-PGJ(2)-induced apoptosis and inhibition of cell proliferation in OUMS-27 cells. The preliminary results of cDNA microarray analysis showed the down-regulation of anti-apoptotic Bcl-xL and up-regulation of pro-apoptotic Bax in the process of 15d-PGJ(2)-induced apoptosis. These changes were further confirmed at mRNA and protein levels by RT-PCR and Western blot analysis, respectively. Among cyclin-dependent kinase inhibitors, p21 was induced and up-regulated by 15d-PGJ(2), but p16 and p27 were not changed, suggesting that the involvement of p21 in inhibition of cell proliferation. Activation of caspase-3 by 15d-PGJ(2) was partly, but not completely, blocked by PPAR gamma antagonist (GW9662) suggesting the 15d-PGJ(2) exerted its effect by PPAR gamma-dependent and -independent pathways. Interestingly, immunohistochemical study on human chondrosarcoma samples revealed that Bcl-xL is frequently expressed by tumor cells. The results of the current study suggest that the potential ability of 15d-PGJ(2) in regulation of cell cycle and inhibition of Bcl-xL expression might be beneficial in the development of novel pharmacological agents for chondrosarcoma.

SYT, a partner of SYT-SSX oncoprotein in synovial sarcomas, interacts with mSin3A, a component of histone deacetylase complex.

Synovial sarcomas are soft-tissue tumors predominantly affecting children and young adults. They are molecular-genetically characterized by the SYT-SSX fusion gene generated from chromosomal translocation t(X; 18) (p11.2; q11.2). When we screened new gene products that interact with SYT or SSX proteins by yeast two-hybrid assay, we found that mSin3A, a component of the histone deacetylase complex, interacts with SYT but not with SSX. These results were confirmed by mammalian two-hybrid and pull-down assays. Analyses with sequential truncated proteins revealed a main mSin3A-interaction region on the SYT amino-terminal 93 amino acids, and another one on the region between 187th amino acid and break point. In luciferase assay, mSin3A repressed the transcriptional activity of reporter promoter mediated by SYT and hBRM/BRG1. Our results suggest that the histone deacetylase complex containing mSin3A may regulate the transcriptional activation mediated by SYT.

Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression.

OBJECTIVE: To examine whether depsipeptide (FK228), a histone deacetylase (HDA) inhibitor, has inhibitory effects on the proliferation of synovial fibroblasts from rheumatoid arthritis (RA) patients, and to examine the effects of systemic administration of FK228 in an animal model of arthritis. METHODS: Autoantibody-mediated arthritis (AMA) was induced in 19 male DBA/1 mice (6-7 weeks old); 10 of them were treated by intravenous administration of FK228 (2.5 mg/kg), and 9 were used as controls. The effects of FK228 were examined by radiographic, histologic, and immunohistochemical analyses and arthritis scores. RA synovial fibroblasts (RASFs) were obtained at the time of joint replacement surgery. In vitro effects of FK228 on cell proliferation were assessed by MTT assay. Cell morphology was examined by light and transmission electron microscopy. The effects on the expression of the cell cycle regulators p16INK4a and p21(WAF1/Cip1) were examined by real-time polymerase chain reaction and Western blot analysis. The acetylation status of the promoter regions of p16INK4a and p21(WAF1/Cip1) were determined by chromatin immunoprecipitation assay. RESULTS: A single intravenous injection of FK228 (2.5 mg/ml) successfully inhibited joint swelling, synovial inflammation, and subsequent bone and cartilage destruction in mice with AMA. FK228 treatment induced histone hyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor alpha and interleukin-1beta in the synovial tissues of mice with AMA. FK228 inhibited the in vitro proliferation of RASFs in a dose-dependent manner. Treatment of cells with FK228 induced the expression of p16INK4a and up-regulated the expression of p21(WAF1/Cip1). These effects of FK228 on p16INK4a and p21(WAF1/Cip1) were related to the acetylation of the promoter region of the genes. CONCLUSION: Our findings strongly suggest that systemic administration of HDA inhibitors may represent a novel therapeutic target in RA by means of cell cycle arrest in RASFs via induction of p16INK4a expression and increase in p21(WAF1/Cip1) expression.