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1.
Cell ; 156(4): 730-43, 2014 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-24529376

RESUMEN

Osteoarthritis (OA), primarily characterized by cartilage degeneration, is caused by an imbalance between anabolic and catabolic factors. Here, we investigated the role of zinc (Zn2+) homeostasis, Zn2+ transporters, and Zn(2+)-dependent transcription factors in OA pathogenesis. Among Zn2+ transporters, the Zn2+ importer ZIP8 was specifically upregulated in OA cartilage of humans and mice, resulting in increased levels of intracellular Zn2+ in chondrocytes. ZIP8-mediated Zn2+ influx upregulated the expression of matrix-degrading enzymes (MMP3, MMP9, MMP12, MMP13, and ADAMTS5) in chondrocytes. Ectopic expression of ZIP8 in mouse cartilage tissue caused OA cartilage destruction, whereas Zip8 knockout suppressed surgically induced OA pathogenesis, with concomitant modulation of Zn2+ influx and matrix-degrading enzymes. Furthermore, MTF1 was identified as an essential transcription factor in mediating Zn2+/ZIP8-induced catabolic factor expression, and genetic modulation of Mtf1 in mice altered OA pathogenesis. We propose that the zinc-ZIP8-MTF1 axis is an essential catabolic regulator of OA pathogenesis.


Asunto(s)
Osteoartritis/metabolismo , Osteoartritis/patología , Transducción de Señal , Proteínas ADAM/metabolismo , Anciano , Animales , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Condrocitos/metabolismo , Condrocitos/patología , Humanos , Factores de Transcripción de Tipo Kruppel/metabolismo , Masculino , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Regulación hacia Arriba , Zinc/metabolismo
2.
Nature ; 566(7743): 254-258, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30728500

RESUMEN

Osteoarthritis-the most common form of age-related degenerative whole-joint disease1-is primarily characterized by cartilage destruction, as well as by synovial inflammation, osteophyte formation and subchondral bone remodelling2,3. However, the molecular mechanisms that underlie the pathogenesis of osteoarthritis are largely unknown. Although osteoarthritis is currently considered to be associated with metabolic disorders, direct evidence for this is lacking, and the role of cholesterol metabolism in the pathogenesis of osteoarthritis has not been fully investigated4-6. Various types of cholesterol hydroxylases contribute to cholesterol metabolism in extrahepatic tissues by converting cellular cholesterol to circulating oxysterols, which regulate diverse biological processes7,8. Here we show that the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes is a crucial catabolic regulator of the pathogenesis of osteoarthritis. Osteoarthritic chondrocytes had increased levels of cholesterol because of enhanced uptake, upregulation of cholesterol hydroxylases (CH25H and CYP7B1) and increased production of oxysterol metabolites. Adenoviral overexpression of CH25H or CYP7B1 in mouse joint tissues caused experimental osteoarthritis, whereas knockout or knockdown of these hydroxylases abrogated the pathogenesis of osteoarthritis. Moreover, retinoic acid-related orphan receptor alpha (RORα) was found to mediate the induction of osteoarthritis by alterations in cholesterol metabolism. These results indicate that osteoarthritis is a disease associated with metabolic disorders and suggest that targeting the CH25H-CYP7B1-RORα axis of cholesterol metabolism may provide a therapeutic avenue for treating osteoarthritis.


Asunto(s)
Colesterol/metabolismo , Familia 7 del Citocromo P450/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Osteoartritis/metabolismo , Esteroide Hidroxilasas/metabolismo , Animales , Transporte Biológico , Condrocitos/enzimología , Condrocitos/metabolismo , Masculino , Ratones , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Osteoartritis/enzimología , Osteoartritis/patología , Oxiesteroles/metabolismo , Esteroide Hidroxilasas/deficiencia , Regulación hacia Arriba
3.
Arthroscopy ; 36(6): 1612-1624, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-31785390

RESUMEN

PURPOSE: The purpose of this study was to evaluate the clinical efficacy and safety of treating patients with a cartilage defect of the knee with microfractures and porcine-derived collagen-augmented chondrogenesis technique (C-ACT). METHODS: One hundred participants were randomly assigned to the control group (n = 48, microfracture) or the investigational group (n = 52, C-ACT). Clinical and magnetic resonance imaging (MRI) outcomes were assessed 12 and 24 months postoperatively for efficacy and adverse events. Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) assessment was used to analyze cartilage tissue repair. MRI outcomes for 50% defect filling and repaired tissue/reference cartilage (RT/RC) ratio were quantified using T2 mapping. Clinical outcomes were assessed using the visual analogue scale (VAS) for pain and 20% improvement, minimal clinically important difference (MCID), and patient acceptable symptom state for Knee Injury and Osteoarthritis Outcome Score (KOOS) and the International Knee Documentation Committee score. RESULTS: MOCART scores in the investigation group showed improved defect repair and filling (P = .0201), integration with the border zone (P = .0062), and effusion (P = .0079). MRI outcomes showed that the odds ratio (OR) for ≥50% defect filling at 12 months was statistically higher in the investigation group (OR 3.984, P = .0377). Moreover, the likelihood of the RT/RC OR becoming ≥1 was significantly higher (OR 11.37, P = .0126) in the investigation group. At 24 months postoperatively, the OR for the VAS 20% improvement rate was significantly higher in the investigational group (OR 2.808, P = .047). Twenty-three patients (52.3%) in the control group and 35 (77.8%) in the investigation group demonstrated more than the MCID of KOOS pain from baseline to 1 year postoperatively, with a significant difference between groups (P = .0116). CONCLUSION: In this multicenter randomized trial, the addition of C-ACT resulted in better filling of cartilage defect of the knee joint. LEVEL OF EVIDENCE: Level Ⅰ, Multicenter Randomized Controlled Trial.


Asunto(s)
Enfermedades de los Cartílagos/terapia , Cartílago Articular/trasplante , Condrogénesis/fisiología , Colágeno/farmacología , Fracturas por Estrés/terapia , Articulación de la Rodilla/cirugía , Animales , Enfermedades de los Cartílagos/complicaciones , Enfermedades de los Cartílagos/diagnóstico , Femenino , Estudios de Seguimiento , Fracturas por Estrés/etiología , Fracturas por Estrés/patología , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Porcinos , Trasplante Autólogo , Resultado del Tratamiento
4.
Ann Rheum Dis ; 78(3): 421-428, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30610061

RESUMEN

OBJECTIVE: Osteoarthritis (OA) appears to be associated with various metabolic disorders, but the potential contribution of amino acid metabolism to OA pathogenesis has not been clearly elucidated. Here, we explored whether alterations in the amino acid metabolism of chondrocytes could regulate OA pathogenesis. METHODS: Expression profiles of amino acid metabolism-regulating genes in primary-culture passage 0 mouse chondrocytes were examined by microarray analysis, and selected genes were further characterised in mouse OA chondrocytes and OA cartilage of human and mouse models. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) or intra-articular (IA) injection of adenoviruses expressing catabolic regulators. The functional consequences of arginase II (Arg-II) were examined in Arg2-/- mice and those subjected to IA injection of an adenovirus encoding Arg-II (Ad-Arg-II). RESULTS: The gene encoding Arg-II, an arginine-metabolising enzyme, was specifically upregulated in chondrocytes under various pathological conditions and in OA cartilage from human patients with OA and various mouse models. Adenovirus-mediated overexpression of Arg-II in mouse joint tissues caused OA pathogenesis, whereas genetic ablation of Arg2 in mice (Arg2-/-) abolished all manifestations of DMM-induced OA. Mechanistically, Arg-II appears to cause OA cartilage destruction at least partly by upregulating the expression of matrix-degrading enzymes (matrix metalloproteinase 3 [MMP3] and MMP13) in chondrocytes via the nuclear factor (NF)-κB pathway. CONCLUSIONS: Our results indicate that Arg-II is a crucial regulator of OA pathogenesis in mice. Although chondrocytes of human and mouse do not identically, but similarly, respond to Arg-II, our results suggest that Arg-II could be a therapeutic target of OA pathogenesis.


Asunto(s)
Arginasa/fisiología , Artritis Experimental/enzimología , Cartílago Articular/enzimología , Condrocitos/enzimología , Osteoartritis/enzimología , Animales , Artritis Experimental/inducido químicamente , Modelos Animales de Enfermedad , Humanos , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones , Osteoartritis/inducido químicamente , Regulación hacia Arriba
5.
Cell Commun Signal ; 17(1): 158, 2019 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-31779635

RESUMEN

Following publication of the original article [1], the authors reported that Figs. 3 and 6 are incorrect.

6.
J Arthroplasty ; 34(12): 2999-3003, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31401038

RESUMEN

BACKGROUND: As the frequency of total knee arthroplasty (TKA) is increasing, long-term follow-up of patients has become essential, and the frequency of revision total knee arthroplasty (R-TKA) due to the occurrence of various complications has also increased. There is controversy regarding which approach has minimal complications and an adequate visual field in R-TKA. Therefore, we compared the clinical and radiological results between the extensile medial parapatellar (EMP) approach and tibial tubercle osteotomy (TTO) for R-TKA. METHODS: Between March 1, 2000, and December 31, 2015, we compared 35 patients who underwent the EMP approach and 31 who underwent the TTO approach for R-TKA. In this study, the preoperative range of motion (ROM) was an important criterion for the choice of approach in R-TKA. The EMP approach was applied to patients with a ROM above 60°. The TTO approach was applied to patients with knee flexion limited to 0°-30°. We clinically assessed knee ROM, Knee Society scores, and Hospital for Special Surgery scores at the time of the last follow-up. We radiographically measured femorotibial alignment and patellar height. We also examined the complication rates. The average length of the TTO was 1.0 × 2.5 cm × 10 cm. We used 3 or more 3.5-mm half-threaded screws. RESULTS: The mean postoperative ROM of the knee joint at the time of the last follow-up was 103° (flexion contracture 5° and further flexion 108°) in the group that underwent the EMP approach and 101° (flexion contracture 4° and further flexion 109°) in the group that underwent the TTO approach. The mean Knee Society scores were 86 (71-96) and 85 (72-94), and the mean Hospital for Special Surgery scores were 82 (70-93) and 83 (68-92) for the 2 groups, respectively, with no statistically significant difference. The mean femorotibial angles were 0.6° (±3.3°) and 0.1° (±2.9°), and the mean Insall-Salvati ratios were 1.0 (±0.34) and 0.8 (±0.14), respectively, with no statistically significant difference. The group that underwent TTO achieved bone union at an average of 11.8 weeks after surgery. In the group that underwent the EMP approach, 2 patients had extensor lag of more than 10°. In the group that underwent TTO, 2 subjects had skin necrosis at the operative site. CONCLUSION: The clinical and radiological outcomes were similar in the 2 groups after R-TKA. To increase the ROM and obtain adequate exposure, TTO is also considered a useful surgical approach. However, complications related to TTO should be minimized. LEVEL OF EVIDENCE: Therapeutic level III, retrospective comparative study.


Asunto(s)
Artroplastia de Reemplazo de Rodilla , Artroplastia de Reemplazo de Rodilla/efectos adversos , Humanos , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/cirugía , Osteotomía/efectos adversos , Rótula/cirugía , Rango del Movimiento Articular , Estudios Retrospectivos , Tibia/cirugía , Resultado del Tratamiento
7.
Cell Biochem Funct ; 36(7): 366-376, 2018 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-30264402

RESUMEN

Even though increasing evidence indicates the importance of peroxisomal lipid metabolism in regulating biological and pathological events, its involvement in cartilage development has not been well studied. Here, we identified the importance of peroxisomal function, particularly the functional integrity of ABCD2, in the pathogenesis of osteoarthritis (OA). Knockdown of ABCD2 in OA chondrocytes induced the accumulation of very long chain fatty acids (VLCFAs) and apoptotic cell death. Moreover, knockdown of ABCD2 altered profiles of miRNAs that affect the expression level of ACSL4, a known direct regulator of lipid metabolism. Suppression of ACSL4 in human chondrocytes-induced VLCFA accumulation, MMP-13 expression, and apoptotic cell death. In vivo morph-down of the ACSL4 homologue in zebrafish resulted in significant defects in cartilage development and in vivo knockdown of ACSL4 in cartilage tissue of an OA model mice promoted severe cartilage degradation. In summary, to the best of our knowledge, this is the first report suggesting that the regulatory network among peroxisomal ABCD2:ACSL4:VLCFA serves as a novel regulator of cartilage homeostasis, and these data may provide novel insights into the role of peroxisomal fatty acid metabolism in pathogenesis of human OA. SIGNIFICANCE OF THE STUDY: Our study indicates that peroxisomal dysfunction is closely related to OA pathogenesis. Particularly, the functional integrity of ABCD2 may play an important role in OA pathogenesis via the accumulation of VLCFAs and stimulation of apoptotic death through altering profiles of miRNAs that target ACSL4. Our findings suggest that targeting the regulatory network among the peroxisomal ABCD2:ACSL4:VLCFA axis may provide a new potential therapeutic strategy for OA pathogenesis.


Asunto(s)
Subfamilia D de Transportadores de Casetes de Unión al ATP/metabolismo , Coenzima A Ligasas/metabolismo , Metabolismo de los Lípidos , MicroARNs/metabolismo , Osteoartritis/metabolismo , Subfamilia D de Transportadores de Casetes de Unión al ATP/genética , Adulto , Animales , Apoptosis , Condrocitos/metabolismo , Condrocitos/patología , Coenzima A Ligasas/genética , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , Ratones , MicroARNs/genética , Persona de Mediana Edad , Osteoartritis/genética , Osteoartritis/patología , Peroxisomas/metabolismo , Pez Cebra
8.
BMC Musculoskelet Disord ; 19(1): 69, 2018 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-29499681

RESUMEN

BACKGROUND: We report the successful use of allograft-prosthesis composite (APC) and structural femoral head allografting in the bilateral reconstruction of large femoral and tibial uncontained defects during revision total knee arthroplasty (RTKA). CASE PRESENTATION: A 67-year-old female with degenerative arthritis underwent bilateral total knee arthroplasty (TKA) using the Press Fit Condylar (PFC) modular knee system at our clinic in March, 1996. At 8 years postoperatively, the patient presented with painful, bilateral varus knees, with swelling, limited passive range of motion (ROM), and severe instability. We treated to reconstruct both knee using a femoral head allograft at the tibial site, a structural distal femoral allograft at the femoral site, and a varus-valgus constrained (VVC) prosthesis with cement. At the 10-year follow up, we found no infection, graft failure, loosening of implants, in spite of using massive bilateral structural femoral head allografts in RTKA. CONCLUSION: The use of APC enabled a stable and durable reconstruction in this uncommon presentation with large femoral bone deficiencies encountered during a RTKA.


Asunto(s)
Artroplastia de Reemplazo de Rodilla/métodos , Trasplante Óseo/métodos , Cabeza Femoral/trasplante , Prótesis de la Rodilla , Reoperación/métodos , Tibia/cirugía , Anciano , Aloinjertos/trasplante , Artroplastia de Reemplazo de Rodilla/instrumentación , Artroplastia de Reemplazo de Rodilla/tendencias , Trasplante Óseo/instrumentación , Trasplante Óseo/tendencias , Femenino , Cabeza Femoral/diagnóstico por imagen , Estudios de Seguimiento , Humanos , Prótesis de la Rodilla/tendencias , Falla de Prótesis/tendencias , Reoperación/instrumentación , Reoperación/tendencias , Tibia/diagnóstico por imagen , Factores de Tiempo
9.
Proc Natl Acad Sci U S A ; 112(30): 9424-9, 2015 Jul 28.
Artículo en Inglés | MEDLINE | ID: mdl-26170306

RESUMEN

Osteoarthritis (OA) is characterized by impairment of the load-bearing function of articular cartilage. OA cartilage matrix undergoes extensive biophysical remodeling characterized by decreased compliance. In this study, we elucidate the mechanistic origin of matrix remodeling and the downstream mechanotransduction pathway and further demonstrate an active role of this mechanism in OA pathogenesis. Aging and mechanical stress, the two major risk factors of OA, promote cartilage matrix stiffening through the accumulation of advanced glycation end-products and up-regulation of the collagen cross-linking enzyme lysyl oxidase, respectively. Increasing matrix stiffness substantially disrupts the homeostatic balance between chondrocyte catabolism and anabolism via the Rho-Rho kinase-myosin light chain axis, consequently eliciting OA pathogenesis in mice. Experimental enhancement of nonenzymatic or enzymatic matrix cross-linking augments surgically induced OA pathogenesis in mice, and suppressing these events effectively inhibits OA with concomitant modulation of matrix degrading enzymes. Based on these findings, we propose a central role of matrix-mediated mechanotransduction in OA pathogenesis.


Asunto(s)
Cartílago Articular/patología , Mecanotransducción Celular , Osteoartritis/patología , Resinas Acrílicas/química , Anciano , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Condrocitos/citología , Colágeno/química , Reactivos de Enlaces Cruzados/química , Genes Reporteros , Productos Finales de Glicación Avanzada/química , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Persona de Mediana Edad , Proteína-Lisina 6-Oxidasa/metabolismo , Factores de Riesgo , Transducción de Señal , Estrés Mecánico
10.
Ann Rheum Dis ; 76(2): 427-434, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-27147707

RESUMEN

OBJECTIVE: The basic leucine zipper transcription factor, ATF-like (BATF), a member of the Activator protein-1 family, promotes transcriptional activation or repression, depending on the interacting partners (JUN-B or C-JUN). Here, we investigated whether the BATF/JUN complex exerts regulatory effects on catabolic and anabolic gene expression in chondrocytes and contributes to the pathogenesis of osteoarthritis (OA). METHODS: Primary cultured mouse chondrocytes were treated with proinflammatory cytokines (interleukin-1ß, IL-6 or tumour necrosis factor-α) or infected with adenoviruses carrying the Batf gene (Ad-Batf). Expression of BATF and JUN was examined in human and mouse experimental OA cartilage samples. Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of Ad-Batf. The chromatin immunoprecipitation assay was used to examine the binding of BATF and JUN to the promoter regions of candidate genes. RESULTS: Overexpression of BATF, which forms a heterodimeric complex with JUN-B and C-JUN, induced upregulation of matrix-degrading enzymes and downregulation of cartilage matrix molecules in chondrocytes. BATF expression in mouse joint tissues promoted OA cartilage destruction, and conversely, knockout of Batf in mice suppressed experimental OA. Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice. CONCLUSIONS: BATF/JUN-B and BATF/C-JUN complexes play important roles in OA cartilage destruction through regulating anabolic and catabolic gene expression in chondrocytes. Our findings collectively support the utility of BATF as a therapeutic target for OA.


Asunto(s)
Artritis Experimental/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Cartílago Articular/metabolismo , Condrocitos/metabolismo , Osteoartritis/genética , Proteínas Proto-Oncogénicas c-jun/genética , Animales , Artritis Experimental/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/efectos de los fármacos , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Cartílago Articular/citología , Cartílago Articular/efectos de los fármacos , Células Cultivadas , Condrocitos/efectos de los fármacos , Citocinas/farmacología , Humanos , Interleucina-1beta/farmacología , Interleucina-6/farmacología , Masculino , Ratones , Ratones Noqueados , Osteoartritis/metabolismo , Proteínas Proto-Oncogénicas c-jun/efectos de los fármacos , Proteínas Proto-Oncogénicas c-jun/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Necrosis Tumoral alfa/farmacología
11.
PLoS Biol ; 12(6): e1001881, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24914685

RESUMEN

Rheumatoid arthritis (RA) is a systemic autoimmune disorder that manifests as chronic inflammation and joint tissue destruction. However, the etiology and pathogenesis of RA have not been fully elucidated. Here, we explored the role of the hypoxia-inducible factors (HIFs), HIF-1α (encoded by HIF1A) and HIF-2α (encoded by EPAS1). HIF-2α was markedly up-regulated in the intimal lining of RA synovium, whereas HIF-1α was detected in a few cells in the sublining and deep layer of RA synovium. Overexpression of HIF-2α in joint tissues caused an RA-like phenotype, whereas HIF-1α did not affect joint architecture. Moreover, a HIF-2α deficiency in mice blunted the development of experimental RA. HIF-2α was expressed mainly in fibroblast-like synoviocytes (FLS) of RA synovium and regulated their proliferation, expression of RANKL (receptor activator of nuclear factor-κB ligand) and various catabolic factors, and osteoclastogenic potential. Moreover, HIF-2α-dependent up-regulation of interleukin (IL)-6 in FLS stimulated differentiation of TH17 cells-crucial effectors of RA pathogenesis. Additionally, in the absence of IL-6 (Il6-/- mice), overexpression of HIF-2α in joint tissues did not cause an RA phenotype. Thus, our results collectively suggest that HIF-2α plays a pivotal role in the pathogenesis of RA by regulating FLS functions, independent of HIF-1α.


Asunto(s)
Artritis Experimental/etiología , Artritis Reumatoide/etiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Animales , Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Diferenciación Celular , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Interleucina-6/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Fenotipo , Membrana Sinovial/metabolismo , Células Th17/citología , Regulación hacia Arriba
13.
Ann Rheum Dis ; 75(11): 2045-2052, 2016 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26903440

RESUMEN

OBJECTIVE: The zinc-ZIP8-MTF1 axis induces metallothionein (MT) expression and is a catabolic regulator of experimental osteoarthritis (OA) in mice. The main aim of the current study was to explore the roles and underlying molecular mechanisms of MTs in OA pathogenesis. METHODS: Experimental OA in mice was induced by destabilisation of the medial meniscus or intra-articular injection of adenovirus carrying a target gene (Ad-Zip8, Ad-Mtf1, Ad-Epas1, Ad-Nampt, Ad-Mt1 or Ad-Mt2) into wild type, Zip8fl/fl; Col2a1-Cre, Mtf1fl/fl; Col2a1-Cre and Mt1/Mt2 double knockout mice. Primary cultured mouse chondrocytes were infected with Ad-Mt1 or Ad-Mt2, and gene expression profiles analysed via microarray and reverse transcription-PCR. Proteins in human and mouse OA cartilage were identified via immunostaining. Chondrocyte apoptosis in OA cartilage was determined using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick end labelling (TUNEL). RESULTS: MTs were highly expressed in human and mouse OA cartilage. Hypoxia-inducible factor 2α, nicotinamide phosphoribosyltransferase and several proinflammatory cytokine pathways, as well as the zinc-ZIP8-MTF1 axis were identified as upstream regulators of MT expression. Genetic deletion of Mt1 and Mt2 enhanced cartilage destruction through increasing chondrocyte apoptosis. Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA. CONCLUSIONS: MTs play an antiapoptotic role in post-traumatic OA. However, aberrant and chronic upregulation of MT2 triggers an imbalance between chondrocyte anabolism and catabolism, consequently accelerating OA development. Our findings collectively highlight pleiotropic roles of MTs as regulators of chondrocyte apoptosis as well as catabolic and anabolic pathways during OA pathogenesis.


Asunto(s)
Apoptosis/genética , Artritis Experimental/genética , Condrocitos/metabolismo , Pleiotropía Genética , Metalotioneína/metabolismo , Osteoartritis/genética , Animales , Artritis Experimental/patología , Cartílago Articular/metabolismo , Humanos , Ratones , Ratones Noqueados , Osteoartritis/patología , Reacción en Cadena en Tiempo Real de la Polimerasa
14.
J Arthroplasty ; 31(12): 2778-2783, 2016 12.
Artículo en Inglés | MEDLINE | ID: mdl-27378646

RESUMEN

BACKGROUND: This study was conducted to assess the clinical and radiological results of total knee arthroplasty (TKA) with an allogeneic bone graft using varus-valgus constrained (VVC) prostheses in knees with severe bone defects and unstable neuropathy. METHODS: This study included 20 knees of 16 patients who underwent TKA between August 2001 and January 2006 due to unstable knees with severe bone destruction resulting from neuropathic arthritis. At the time of surgery, the mean age of the patients was 56 years. The mean length of the follow-up period was 10.7 years. A VVC condylar prosthesis was used with an allogeneic femoral head graft to reconstruct large bony defects. Clinical results were evaluated using the Hospital for Special Surgery, Knee Society function, and Western Ontario and McMaster Universities Osteoarthritis scores. Three-dimensional computed tomography was used to evaluate the radiological parameters, which included the tibiofemoral angle, loosening or osteolysis of components, and incorporation of the bone graft. RESULTS: The preoperative mean Hospital for Special Surgery, Knee Society function, and Western Ontario and McMaster Universities Osteoarthritis scores were 40.5, 43.2, and 78.3, respectively, and these scores improved to 86.0, 64.6, and 33.8, respectively at the final follow-up. The mean postoperative alignment was 6.1° of valgus angulation. One knee had instability, another knee had partial bony absorption, which was confirmed using 3-dimensional computed tomography, and the other 18 cases (90%) had satisfactory results. No cases experienced radiolucency, fracture, or infection. CONCLUSIONS: TKA with an allogeneic bone graft using a VVC prosthesis provides a viable option for the treatment of severe bone defects with soft-tissue insufficiency in neuropathic knee arthropathy.


Asunto(s)
Artropatía Neurógena/cirugía , Artroplastia de Reemplazo de Rodilla/métodos , Trasplante Óseo , Cabeza Femoral/cirugía , Prótesis de la Rodilla , Artropatía Neurógena/complicaciones , Enfermedades Óseas/cirugía , Enfermedades de los Cartílagos/cirugía , Femenino , Cabeza Femoral/diagnóstico por imagen , Estudios de Seguimiento , Humanos , Inestabilidad de la Articulación/etiología , Inestabilidad de la Articulación/cirugía , Articulación de la Rodilla/diagnóstico por imagen , Articulación de la Rodilla/cirugía , Masculino , Persona de Mediana Edad , Trasplante Homólogo
15.
Ann Rheum Dis ; 74(3): 595-602, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24347567

RESUMEN

OBJECTIVE: Hypoxia-inducible factor 2α (HIF-2α), encoded by Epas1, causes osteoarthritic cartilage destruction by regulating the expression of matrix-degrading enzymes. We undertook this study to explore the role of nicotinamide phosphoribosyltransferase (NAMPT or visfatin) in HIF-2α-mediated osteoarthritic cartilage destruction. METHODS: The expression of HIF-2α, NAMPT and matrix-degrading enzymes was determined at the mRNA and protein levels in human osteoarthritis (OA) cartilage, mouse experimental OA cartilage and primary cultured mouse chondrocytes. Experimental OA in mice was induced by destabilisation of the medial meniscus (DMM) surgery or intra-articular injection of Ad-Epas1 or Ad-Nampt in wild-type, Epas1(+/-), Epas1(fl/fl);Col2a1-Cre and Col2a1-Nampt transgenic (TG) mice. Primary cultured mouse chondrocytes were treated with recombinant NAMPT protein or were infected with adenoviruses. RESULTS: We found that the Nampt gene is a direct target of HIF-2α in articular chondrocytes and OA cartilage. NAMPT protein, in turn, increased mRNA levels and activities of MMP3, MMP12 and MMP13 in chondrocytes, an action that was necessary for HIF-2α-induced expression of catabolic enzymes. Gain-of-function studies (intra-articular injection of Ad-Nampt; Col2a1-Nampt TG mice) and loss-of-function studies (intra-articular injection of the NAMPT inhibitor FK866) demonstrated that NAMPT is an essential catabolic regulator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery. CONCLUSIONS: Our findings indicate that NAMPT, whose corresponding gene is a direct target of HIF-2α, plays an essential catabolic role in OA pathogenesis and acts as a crucial mediator of osteoarthritic cartilage destruction caused by HIF-2α or DMM surgery.


Asunto(s)
Artritis Experimental/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Cartílago Articular/metabolismo , Condrocitos/metabolismo , Colágeno Tipo II/metabolismo , Nicotinamida Fosforribosiltransferasa/metabolismo , Osteoartritis/metabolismo , Agrecanos/metabolismo , Animales , Cartílago Articular/citología , Humanos , Metaloproteinasas de la Matriz/metabolismo , Meniscos Tibiales/cirugía , Ratones , Ratones Endogámicos C57BL , Regulación hacia Arriba
16.
J Biol Chem ; 287(15): 11751-60, 2012 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-22298781

RESUMEN

Chondrocytes, a unique cell type in cartilage tissue, are responsible for the regulation of anabolic and catabolic homeostasis in cartilage-specific extracellular matrix synthesis. Activation of Wnt/ß-catenin signaling induces dedifferentiation of articular chondrocytes, resulting in suppression of type II collagen expression. We have shown previously that α-catenin inhibits ß-catenin-Tcf/Lef (T-cell factor/lymphoid-enhancing factor) transcriptional activity in articular chondrocytes with a concomitant recovery of type II collagen expression. In the current study, we elucidated the mechanism underlying this inhibition of ß-catenin-Tcf/Lef transcriptional activity by α-catenin, showing that it requires direct interaction between α-catenin and ß-catenin. We further showed that it involves recruitment of Gli3R, the short transcription-repressing form of the transcription factor Gli3, to ß-catenin by α-catenin. The resulting inhibition of ß-catenin transcriptional activity leads to increased expression of type II collagen. Gli3R and α-catenin actions are co-dependent: both are necessary for the observed inhibitory effects on ß-catenin transcriptional activity. Reducing Gli3R expression levels through activation of Indian Hedgehog (Ihh) signaling also is sufficient to activate ß-catenin transcriptional activity, suggesting that the ternary complex, Gli3R·α-catenin·ß-catenin, mediates Ihh-dependent activation of Wnt/ß-catenin signaling in articular chondrocytes. Collectively, this study shows that α-catenin functions as a nuclear factor that recruits the transcriptional repressor Gli3R to ß-catenin to inhibit ß-catenin transcriptional activity and dedifferentiation of articular chondrocytes. Finally, osteoarthritic cartilage showed elevated levels of ß-catenin and decreased levels of α-catenin and Gli3R, suggesting that decreased levels of α-catenin and Gli3R levels contribute to increased ß-catenin transcriptional activity during osteoarthritic cartilage destruction.


Asunto(s)
Condrocitos/metabolismo , Colágeno Tipo II/genética , Regulación de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Factores de Transcripción TCF/metabolismo , alfa Catenina/metabolismo , beta Catenina/metabolismo , Animales , Cartílago Articular/metabolismo , Cartílago Articular/patología , Desdiferenciación Celular , Células Cultivadas , Condrocitos/fisiología , Colágeno Tipo II/metabolismo , Expresión Génica , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/fisiología , Humanos , Ratones , Ratones Endogámicos C57BL , Complejos Multiproteicos/metabolismo , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Osteoartritis/metabolismo , Osteoartritis/patología , Cultivo Primario de Células , Unión Proteica , Conejos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Transcripción Genética , Proteína Gli3 con Dedos de Zinc , alfa Catenina/genética , beta Catenina/genética
17.
J Biol Chem ; 287(15): 12501-9, 2012 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-22351754

RESUMEN

MicroRNAs (miRNAs) have been implicated in various cellular processes, such as cell fate determination, cell death, and tumorigenesis. In the present study, we investigated the role of miRNA-34a (miR-34a) in the reorganization of the actin cytoskeleton, which is essential for chondrocyte differentiation. miRNA arrays to identify genes that appeared to be up-regulated or down-regulated during chondrogenesis were applied with chondrogenic progenitors treated with JNK inhibitor. PNA-based antisense oligonucleotides and miRNA precursor were used for investigation of the functional roles of miR-34a. We found that, in chick chondroprogenitors treated with JNK inhibitor, which suppresses chondrogenic differentiation, the expression levels of miR-34a and RhoA1 are up-regulated through modulation of Rac1 expression. Blockade of miR-34a via the use of PNA-based antisense oligonucleotides was associated with decreased protein expression of RhoA (a known modulator of stress fiber expression), down-regulation of stress fibers, up-regulation of Rac1, and recovery of protein level of type II collagen. miR-34a regulates RhoA/Rac1 cross-talk and negatively modulates reorganization of the actin cytoskeleton, which is one of the essential processes for establishing chondrocyte-specific morphology.


Asunto(s)
Condrocitos/metabolismo , MicroARNs/fisiología , Receptor Cross-Talk , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rhoA/metabolismo , Animales , Diferenciación Celular , Células Cultivadas , Embrión de Pollo , Condrogénesis , Expresión Génica , Regulación de la Expresión Génica , Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Mesodermo/citología , MicroARNs/genética , MicroARNs/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Fibras de Estrés/metabolismo , Proteína de Unión al GTP rhoA/genética
18.
Biochem Biophys Res Commun ; 431(2): 210-4, 2013 Feb 08.
Artículo en Inglés | MEDLINE | ID: mdl-23313477

RESUMEN

MicroRNAs are endogenous gene regulators that have been implicated in various developmental and pathological processes. However, the precise identities and functions of the miRNAs involved in cartilage development are not yet well understood. Here, we report that miR-181b regulates chondrocyte differentiation and maintains cartilage integrity, and is thus a potent therapeutic target. MiR-181b was significantly down-regulated during chondrogenic differentiation of TGF-ß3-stimulated limb mesenchymal cells, but it was significantly up-regulated in osteoarthritic chondrocytes isolated from the cartilage of osteoarthritis patients. The use of a mimic or an inhibitor to alter miR-181b levels in chondroblasts and articular chondrocytes showed that attenuation of miR-181b reduced MMP-13 expression while inducing type II collagen expression. Furthermore, over-expression of anti-miR-181b significantly reduced the cartilage destruction caused by DMM surgery in mice. In sum, our data suggest that miR-181b is a negative regulator of cartilage development, and that inhibition of miR-181b could be an effective therapeutic strategy for cartilage-related disease.


Asunto(s)
Cartílago/crecimiento & desarrollo , Diferenciación Celular , Condrocitos/citología , Condrogénesis , MicroARNs/fisiología , Animales , Cartílago/citología , Células Cultivadas , Embrión de Pollo , Condrocitos/efectos de los fármacos , Humanos , Ratones , Factor de Crecimiento Transformador beta3/farmacología
19.
J Biomed Sci ; 20: 31, 2013 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-23688035

RESUMEN

BACKGROUND: Even though osteoarthritis (OA) is the most common musculoskeletal dysfunction, there are no effective pharmacological treatments to treat OA due to lack of understanding in OA pathology. To better understand the mechanism in OA pathogenesis and investigate its effective target, we analyzed miRNA profiles during OA pathogenesis and verify the role and its functional targets of miR-488. RESULTS: Human articular chondrocytes were obtained from cartilage of OA patients undergoing knee replacement surgery and biopsy samples of normal cartilage and the expression profile of miRNA was analyzed. From expression profile, most potent miR was selected and its target and functional role in OA pathogenesis were investigated using target validation system and OA animal model system. Among miRNAs tested, miR-488 was significantly decreased in OA chondrocytes Furthermore, we found that exposure of IL-1ß was also suppressed whereas exposure of TGF-ß3 induced the induction of miR-488 in human articular chondrocytes isolated from biopsy samples of normal cartilages. Target validation study showed that miR-488 targets ZIP8 and suppression of ZIP8 in OA animal model showed the reduced cartilage degradation. Target validation study showed that miR-488 targets ZIP8 and suppression of ZIP8 in OA animal model showed the reduced cartilage degradation. CONCLUSIONS: miR-488 acts as a positive role for chondrocyte differentiation/cartilage development by inhibiting MMP-13 activity through targeting ZIP-8.


Asunto(s)
Proteínas de Transporte de Catión/genética , Condrocitos/metabolismo , MicroARNs/metabolismo , Osteoartritis/metabolismo , Osteoartritis/patología , Animales , Proteínas de Transporte de Catión/metabolismo , Condrocitos/patología , Humanos , Interleucina-1beta/metabolismo , Masculino , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Ratones , MicroARNs/genética , Osteoartritis/genética , Factor de Crecimiento Transformador beta3/metabolismo
20.
Cell Commun Signal ; 11: 66, 2013 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-24007463

RESUMEN

BACKGROUND: Studies have shown the roles of miR-9 and its validated target, protogenin (PRTG) in the differentiation of chondroblasts to chondrocyte and in the pathogenesis of osteoarthritis (OA). We hypothesized that miR-9 plays a distinct role in endochondral ossification and OA pathogenesis and the present study was undertaken to identify this role. In the studies, chondroblasts were isolated from limb bud of chick and mouse embryos and articular chondrocytes were isolated from rabbit and human cartilage. Osteoarthritic chondrocytes were isolated from cartilage from patients undergoing total knee replacement. Using these cells, we analyzed the changes in the expression of genes and proteins, tested the expression level of miR-9, and applied a target validation system. We also performed functional study of miR-9 and PRTG. RESULTS: With the progression of chondrogenesis, decreased miR-9 level was observed at the time of numerous apoptotic cell deaths. And chondrocytes isolated from normal human articular cartilage expressed miR-9, and this expression was significantly reduced in OA chondrocytes, especially decreased its expression in parallel with the degree of cartilage degradation. Over-expression of PRTG induced the activation of caspase-3 signaling and increased apoptosis. However, the co-treatment with the miR-9 precursor or PRTG-specific siRNA blocked this apoptotic signaling. CONCLUSION: This study shows that PRTG is regulated by miR-9, plays an inhibitory action on survival of chondroblasts and articular chondrocytes during chondrogenesis and OA pathogenesis.


Asunto(s)
Condrocitos/metabolismo , Proteínas de la Membrana/metabolismo , MicroARNs/metabolismo , Osteoartritis/metabolismo , Anciano , Animales , Apoptosis/fisiología , Cartílago/metabolismo , Diferenciación Celular/fisiología , Supervivencia Celular/fisiología , Pollos , Condrocitos/citología , Humanos , Proteínas de la Membrana/genética , Ratones , MicroARNs/genética , Persona de Mediana Edad , Conejos
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