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PURPOSE OF REVIEW: The interaction between joint injuries and posttraumatic osteoarthritis (PTOA) is generally thought to be mechanical in nature, however, surgical intervention has little effect on the development of PTOA. Little is known about the biological underpinning of how meniscus and anterior cruciate ligament (ACL) tears lead to cartilage degeneration. This review summarizes the latest findings regarding biological factors that influence how the knee responds to meniscus and ligament injuries, how meniscus and/or ACL tears turn the joint in the direction of PTOA and whether patient risk for PTOA after meniscus/ACL injury can be predicted. RECENT FINDINGS: Literature indicates that numerous intrinsic and extrinsic factors are associated with the biological response of the knee to injuries associated with PTOA. Gene/protein biomarkers provide insight into the biologic response of the knee to meniscus/ACL tears and the relationship to osteoarthritis in at-risk patients. Animal studies detail the time-course of disease pathogenesis and inform about the molecules that potentially alter the course of disease. SUMMARY: The molecular metabolic state of the meniscus/ACL after injury is associated with several biological factors. The limited studies to date provide initial evidence on the early molecular manifestations of injury, suggesting possible mechanisms for further study.
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Lesiones del Ligamento Cruzado Anterior/complicaciones , Menisco/lesiones , Osteoartritis/etiología , Lesiones de Menisco Tibial/complicaciones , Animales , Humanos , Modelos Animales , Investigación Biomédica TraslacionalRESUMEN
Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/ß-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide-siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide-siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.
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OBJECTIVE: To investigate a targeted set of biochemical biomarkers as predictors of clinically relevant osteoarthritis (OA) progression. METHODS: Eighteen biomarkers were measured at baseline, 12â months (M) and 24â M in serum (s) and/or urine (u) of cases (n=194) from the OA initiative cohort with knee OA and radiographic and persistent pain worsening from 24 to 48â M and controls (n=406) not meeting both end point criteria. Primary analyses used multivariable regression models to evaluate the association between biomarkers (baseline and time-integrated concentrations (TICs) over 12 and 24â M, transposed to z values) and case status, adjusted for age, sex, body mass index, race, baseline radiographic joint space width, Kellgren-Lawrence grade, pain and pain medication use. For biomarkers with adjusted p<0.1, the c-statistic (area under the curve (AUC)), net reclassification index and the integrated discrimination improvement index were used to further select for hierarchical multivariable discriminative analysis and to determine the most predictive and parsimonious model. RESULTS: The 24â M TIC of eight biomarkers significantly predicted case status (ORs per 1 SD change in biomarker): sCTXI 1.28, sHA 1.22, sNTXI 1.25, uC2C-HUSA 1.27, uCTXII, 1.37, uNTXI 1.29, uCTXIα 1.32, uCTXIß 1.27. 24 M TIC of uCTXII (1.47-1.72) and uC2C-Human Urine Sandwich Assay (HUSA) (1.36-1.50) both predicted individual group status (pain worsening, joint space loss and their combination). The most predictive and parsimonious combinatorial model for case status consisted of 24 M TIC uCTXII, sHA and sNTXI (AUC 0.667 adjusted). Baseline uCTXII and uCTXIα both significantly predicted case status (OR 1.29 and 1.20, respectively). CONCLUSIONS: Several systemic candidate biomarkers hold promise as predictors of pain and structural worsening of OA.
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Biomarcadores/metabolismo , Osteoartritis de la Rodilla/diagnóstico , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoartritis de la Rodilla/diagnóstico por imagen , Dimensión del Dolor/métodos , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Radiografía , Sensibilidad y Especificidad , Índice de Severidad de la EnfermedadRESUMEN
Purpose/Aim: Meniscus tears are a common injury to the knee associated with the development of osteoarthritis. Gene expression in the injured meniscus may be associated with early degeneration in the articular cartilage. The purpose of this study was to test the hypothesis that gene expression in meniscus tears is associated with early degenerative changes in the articular cartilage at the time of partial meniscectomy. MATERIALS AND METHODS: Torn meniscus was removed at the time of partial meniscectomy in 68 patients without radiographic osteoarthritis. Meniscal mRNA expression was measured by quantitative PCR for multiple molecular markers of osteoarthritis and cartilage homeostasis. The presence of early degenerative changes in the knee was recorded by X-ray (N = 63), magnetic resonance imaging (MRI, N = 48), and arthroscopy (N = 63). Gene expression was tested for correlation with the presence/absence of degenerative changes after adjusting for age, sex, and body mass index. RESULTS: Overall gene expression varied significantly with degenerative changes based on X-ray (P = 0.047) and MRI (P = 0.018). The linear combination of gene variation was also significant. However, only adiponectin (ADIPOQ) (P = 0.015) was expressed at a significantly lower level in patients with chondrosis on MRI, while the expression of ADIPOQ (P = 0.035) and resistin (RETN) (P = 0.017) was higher in patients with early degenerative changes on X-ray. None of the genes varied significantly with presence/absence of chondrosis as measured by arthroscopy. CONCLUSIONS: There is an overall association of gene expression in meniscal tears to early degenerative changes in the knee, but only a limited number of specific genes demonstrate this relationship. The roles of adiponectin and resistin in knee injury and osteoarthritis deserve further study.
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Cartílago Articular/lesiones , Regulación de la Expresión Génica , Traumatismos de la Rodilla/genética , Articulación de la Rodilla/patología , Menisco/lesiones , Adolescente , Adulto , Anciano , Artroscopía , Cartílago Articular/diagnóstico por imagen , Cartílago Articular/patología , Niño , Femenino , Humanos , Traumatismos de la Rodilla/diagnóstico por imagen , Traumatismos de la Rodilla/patología , Articulación de la Rodilla/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Menisco/diagnóstico por imagen , Menisco/patología , Persona de Mediana Edad , Rayos X , Adulto JovenRESUMEN
Cartilage is unique in being established as an avascular tissue during development. Cartilage also has the property of being resistant to tumor invasion with tumors arising on the periphery of cartilage and in bone, but sparing the cartilage. These properties have been investigated for many years beginning in the 1970's. Many anti-angiogenic molecules have been isolated from cartilage in small amounts. Portions of molecules from cartilage also possess anti-angiogenic properties when released from the parent protein by degradative extracellular enzymes. This review highlights a new anti-angiogenic and anti-tumor moiety from cartilage, the NH2-propeptide of type IIB collagen. When released from the procollagen during synthesis, the propeptide has the capacity to act on its own to protect the cartilage by killing of endothelial cell, osteoclasts and tumor cells.
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Colágeno Tipo II/metabolismo , Procolágeno/metabolismo , Secuencia de Aminoácidos , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/farmacología , Condrocitos/metabolismo , Condrocitos/patología , Colágeno Tipo II/química , Colágeno Tipo II/farmacología , Humanos , Modelos Biológicos , Datos de Secuencia Molecular , Procolágeno/química , Procolágeno/farmacologíaRESUMEN
OBJECTIVE: Meniscus tears are associated with a heightened risk of osteoarthritis. This study aimed to advance our understanding of the metabolic state of injured human meniscus at the time of arthroscopic partial meniscectomy through transcriptome-wide analysis of gene expression in relation to the patient's age and degree of cartilage chondrosis. METHODS: The degree of chondrosis of knee cartilage was recorded at the time of meniscectomy in symptomatic patients without radiographic osteoarthritis. RNA preparations from resected menisci (n = 12) were subjected to transcriptome-wide microarray and QuantiGene Plex analyses. Variations in the relative changes in gene expression with age and chondrosis were analyzed, and integrated biologic processes were investigated computationally. RESULTS: We identified a set of genes in torn menisci that were differentially expressed with age and chondrosis. There were 866 genes that were differentially regulated (≥1.5-fold difference and P < 0.05) with age and 49 with chondrosis. In older patients, genes associated with cartilage and skeletal development and extracellular matrix synthesis were repressed, while those involved in immune response, inflammation, cell cycle, and cellular proliferation were stimulated. With chondrosis, genes representing cell catabolism (cAMP catabolic process) and tissue and endothelial cell development were repressed, and those involved in T cell differentiation and apoptosis were elevated. CONCLUSION: Differences in age-related gene expression suggest that in older adults, meniscal cells might dedifferentiate and initiate a proliferative phenotype. Conversely, meniscal cells in younger patients appear to respond to injury, but they maintain the differentiated phenotype. Definitive molecular signatures identified in damaged meniscus could be segregated largely with age and, to a lesser extent, with chondrosis.
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Envejecimiento , Regulación de la Expresión Génica , Traumatismos de la Rodilla/genética , Análisis por Matrices de Proteínas/métodos , Lesiones de Menisco Tibial , Adolescente , Adulto , Factores de Edad , Enfermedades de los Cartílagos/genética , Enfermedades de los Cartílagos/metabolismo , Enfermedades de los Cartílagos/patología , Cartílago Articular/metabolismo , Cartílago Articular/patología , Desdiferenciación Celular/genética , Perfilación de la Expresión Génica , Humanos , Traumatismos de la Rodilla/metabolismo , Traumatismos de la Rodilla/patología , Laceraciones , Meniscos Tibiales/metabolismo , Meniscos Tibiales/patología , Persona de Mediana EdadRESUMEN
To further investigate the regulation role of two chemokine genes CCL3 and CCL4 in chondrocytes in response to resistin, human primary chondrocytes and T/C-28a2 cells were cultured. The function of resistin on the chemokine genes, and the expression of C/EBPß, NF-κB isoforms were tested using qPCR. The methods used to investigate timed co-regulation of C/EBPß and NF-κB were NF-κB inhibitor (IKK-NBD) and C/EBPß inhibitor (SB303580) treatments, and subcellular localization, with or without resistin stimulation. Results showed that resistin could increase the up-regulation of chemokine genes independently. Resistin increased the expression of C/EBPß and NF-κB isoforms. C/EBPß regulated basal activity and steadily increased over time up to 24h with resistin. NF-κB was up-regulated upon induction with resistin, peaking at 4 h. C/EBPß and NF-κB co-enhanced the chemokines expression; inhibition of their activity was additive. The timing of activation in chondrocytes was confirmed by subcellular localization of C/EBPß and c-rel. Chondrocytes react to resistin in a non-restricted cell-specific manner, utilizing C/EBPß and NF-κB in a combinatorial regulation of chemokine gene expression. The activity of C/EBPß is augmented by a transient increase in activity of NF-κB, and both transcription factors act independently on the chemokine genes, CCL3 and CCL4. Thus, resistin stimulates CCL3 and CCL4 through combinatorial regulation of C/EBPß and NF-κB in chondrocytes.
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Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Quimiocinas/genética , FN-kappa B/metabolismo , Resistina/farmacología , Regulación hacia Arriba/efectos de los fármacos , Proteína beta Potenciadora de Unión a CCAAT/antagonistas & inhibidores , Proteína beta Potenciadora de Unión a CCAAT/genética , Cartílago Articular/citología , Células Cultivadas , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Quimiocina CCL4/genética , Quimiocina CCL4/metabolismo , Quimiocinas/metabolismo , Condrocitos/citología , Condrocitos/efectos de los fármacos , Condrocitos/metabolismo , Humanos , Inmunohistoquímica , FN-kappa B/antagonistas & inhibidores , FN-kappa B/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismoRESUMEN
OBJECTIVE: Emerging evidence suggests that genetic components contribute significantly to cartilage degeneration in osteoarthritis pathophysiology, but little information is available on the genetics of cartilage regeneration. Therefore, this study was undertaken to investigate cartilage regeneration in genetic murine models using common inbred strains and a set of recombinant inbred (RI) lines generated from LG/J (healer of ear wounds) and SM/J (nonhealer) inbred mouse strains. METHODS: An acute full-thickness cartilage injury was introduced in the trochlear groove of 8-week-old mice (n=265) through microsurgery. Mouse knee joints were sagittally sectioned and stained with toluidine blue to evaluate regeneration. For the ear wound phenotype, a bilateral 2-mm through-and-through puncture was created in 6-week-old mice (n=229), and healing outcomes were measured after 30 days. Broad-sense heritability and genetic correlations were calculated for both phenotypes. RESULTS: Time-course analysis of the RI mouse lines showed no significant regeneration until 16 weeks after surgery; at that time, the strains could be segregated into 3 categories: good, intermediate, and poor healers. Analysis of heritability (H2) showed that both cartilage regeneration (H2=26%; P=0.006) and ear wound closure (H2=53%; P<0.00001) were significantly heritable. The genetic correlations between the two healing phenotypes for common inbred mouse strains (r=0.92) and RI mouse lines (r=0.86) were found to be extremely high. CONCLUSION: Our findings indicate that articular cartilage regeneration in mice is heritable, the differences between the mouse lines are due to genetic differences, and a strong genetic correlation between the two phenotypes exists, indicating that they plausibly share a common genetic basis. We therefore surmise that LG/J by SM/J intercross mice can be used to dissect the genetic basis of variation in cartilage regeneration.
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Cartílago Articular/fisiología , Oído/fisiología , Regeneración/fisiología , Cicatrización de Heridas/fisiología , Animales , Oído/lesiones , Ratones , Ratones Endogámicos , Fenotipo , Regeneración/genética , Cicatrización de Heridas/genéticaRESUMEN
Site-1 protease (S1P) is a proprotein convertase with essential functions in lipid homeostasis and unfolded protein response pathways. We previously studied a mouse model of cartilage-specific knock-out of S1P in chondroprogenitor cells. These mice exhibited a defective cartilage matrix devoid of type II collagen protein (Col II) and displayed chondrodysplasia with no endochondral bone formation even though the molecular program for endochondral bone development appeared intact. To gain insights into S1P function, we generated and studied a mouse model in which S1P is ablated in postnatal chondrocytes. Postnatal ablation of S1P results in chondrodysplasia. However, unlike early embryonic ablations, the growth plates of these mice exhibit a lack of Ihh, PTHrP-R, and Col10 expression indicating a loss of chondrocyte hypertrophic differentiation and thus disruption of the molecular program required for endochondral bone development. S1P ablation results in rapid growth plate disruption due to intracellular Col II entrapment concomitant with loss of chondrocyte hypertrophy suggesting that these two processes are related. Entrapment of Col II in the chondrocytes of the prospective secondary ossification center precludes its development. Trabecular bone formation is dramatically diminished in the primary spongiosa and is eventually lost. The primary growth plate is eradicated by apoptosis but is gradually replaced by a fully functional new growth plate from progenitor stem cells capable of supporting new bone growth. Our study thus demonstrates that S1P has fundamental roles in the preservation of postnatal growth plate through chondrocyte differentiation and Col II deposition and functions to couple growth plate maturation to trabecular bone development in growing mice.
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Diferenciación Celular , Condrocitos/enzimología , Placa de Crecimiento/enzimología , Osteocondrodisplasias/enzimología , Osteogénesis , Proproteína Convertasas/biosíntesis , Serina Endopeptidasas/biosíntesis , Células Madre/enzimología , Animales , Condrocitos/patología , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Placa de Crecimiento/patología , Ratones , Ratones Noqueados , Especificidad de Órganos/genética , Osteocondrodisplasias/genética , Osteocondrodisplasias/patología , Proproteína Convertasas/genética , Serina Endopeptidasas/genética , Células Madre/patologíaRESUMEN
Cartilage is one of the very few naturally occurring avascular tissues where lack of angiogenesis is the guiding principle for its structure and function. This has attracted investigators who have sought to understand the biochemical basis for its avascular nature, hypothesising that it could be used in designing therapies for treating cancer and related malignancies in humans through antiangiogenic applications. Cartilage encompasses primarily a specialised extracellular matrix synthesised by chondrocytes that is both complex and unique as a result of the myriad molecules of which it is composed. Of these components, a few such as thrombospondin-1, chondromodulin-1, the type XVIII-derived endostatin, SPARC (secreted protein acidic and rich in cysteine) and the type II collagen-derived N-terminal propeptide (PIIBNP) have demonstrated antiangiogenic or antitumour properties in vitro and in vivo preclinical trials that involve several complicated mechanisms that are not completely understood. Thrombospondin-1, endostatin and the shark-cartilage-derived Neovastat preparation have also been investigated in human clinical trials to treat several different kinds of cancers, where, despite the tremendous success seen in preclinical trials, these molecules are yet to show success as anticancer agents. This review summarises the current state-of-the-art antiangiogenic characterisation of these molecules, highlights their most promising aspects and evaluates the future of these molecules in antiangiogenic applications.
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Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Cartílago/química , Neoplasias/tratamiento farmacológico , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/metabolismo , Antineoplásicos/química , Antineoplásicos/metabolismo , Cartílago/metabolismo , Ensayos Clínicos como Asunto , Humanos , Neoplasias/metabolismoRESUMEN
BACKGROUND: Chemotherapy is associated with decreased quality of life (QOL), fatigue, depression, and weight gain in patients with breast cancer. Weight gain is associated with poorer prognosis. Yoga improves QOL, fatigue, and mood in women with breast cancer but its effect on treatment-related weight gain has not been studied. The aim of this trial was to determine the feasibility of personalized yoga therapy in women receiving treatment for early-stage or locally advanced breast cancer and assess its impact on weight gain. METHODS: Thirty women were randomized 1:1 to receive yoga therapy by a certified yoga therapist during treatment or a control group. Participants in the yoga arm were asked to complete three 30 minute yoga sessions weekly (which included movement, breath work, mindfulness, and relaxation) throughout adjuvant or neoadjuvant chemotherapy (N = 29) or endocrine (N = 1); the control arm received breast cancer treatment without yoga. For comparability between participants randomized to yoga therapy, the single patient treated with endocrine therapy was excluded from the analysis. Primary outcomes were feasibility and weight change. Additional outcomes were mood, fatigue, QOL, serum tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP) as immune mediator biomarkers. RESULTS: Mean age was 51.6 years, 75.9% were white and 24.1% were people of color, reflecting the cancer center population. 80% had stage II-III disease. Enrollment was completed in 9 months. Compliance was lower than predicted; however, participants participated in on average 1.7 yoga sessions/week for a mean 15.6 weeks duration. There were no adverse events. Control arm participants gained on average 2.63% body weight during treatment while yoga participants lost 0.14% body weight (weight change = -0.36 in yoga arm vs. 2.89 in standard of care arm, Wilcoxon rank sum test P = .024). Control participants reported increased fatigue and decreased QOL, while yoga participants reported no change in QOL. No significant change in TNF-alpha or CRP was noted in either arm. CONCLUSION: This feasibility study suggests that personalized yoga therapy is beneficial for QOL and weight maintenance among women undergoing chemotherapy for early-stage or locally advanced breast cancer. Weight maintenance associated with yoga therapy may be of clinical significance in this population given the poorer prognosis associated with weight gain in breast cancer survivors. TRIAL REGISTRATION: NIH Clinicaltrials.gov #NCT03262831; August 25, 2017. https://clinicaltrials.gov/ct2/show/NCT03262831.
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Neoplasias de la Mama , Yoga , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/complicaciones , Calidad de Vida , Factor de Necrosis Tumoral alfa , Fatiga/inducido químicamente , Fatiga/terapia , Peso Corporal , Aumento de PesoRESUMEN
Cartilage is resistant to tumor invasion. In the present study, we found that the NH(2)-propeptide of the cartilage-characteristic collagen, type IIB, PIIBNP, is capable of killing tumor cells. The NH(2)-propeptide is liberated into the extracellular matrix prior to deposition of the collagen fibrils. This peptide adheres to and kills cells from chondrosarcoma and cervical and breast cancer cell lines via the integrins alpha(v)beta(5) and alpha(v)beta(3). Adhesion is abrogated by blocking with anti alpha(v)beta(5) and alpha(v)beta(3) antibodies. When alpha(v) is suppressed by small intefering RNA, adhesion and cell killing are blocked. Normal chondrocytes from developing cartilage do not express alpha(v)beta(3) and alpha(v)beta(5) integrins and are thus protected from cell death. Morphological, DNA, and biochemical evidence indicates that the cell death is not by apoptosis but probably by necrosis. In an assay for invasion, PIIBNP reduced the number of cells crossing the membrane. In vivo, in a tumor model for breast cancer, PIIBNP was consistently able to reduce the size of the tumor.
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Cartílago/metabolismo , Integrina alfaVbeta3/metabolismo , Procolágeno/metabolismo , Receptores de Vitronectina/metabolismo , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Adhesión Celular , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Condrosarcoma/metabolismo , Condrosarcoma/patología , Clonación Molecular , ADN Ribosómico/genética , Embrión de Mamíferos/fisiología , Exones/genética , Femenino , Humanos , Integrina alfaVbeta3/antagonistas & inhibidores , Ratones , Fragmentos de Péptidos/metabolismo , ARN/genética , Receptores de Vitronectina/antagonistas & inhibidores , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patologíaRESUMEN
A large set of chemokines is highly up-regulated in human chondrocytes in response to IL-1ß (Sandell, L. J., Xing, X., Franz, C., Davies, S., Chang, L. W., and Patra, D. (2008) Osteoarthr. Cartil. 16, 1560-1571). To investigate the mechanism of transcriptional regulation, deletion constructs of selected chemokine gene promoters, the human CCL3 (MIP-1α) and CCL4 (MIP-1ß), were transfected into human chondrocytes with or without IL-1ß. The results show that an IL-1ß-responsive element is located between bp -300 and -140 of the CCL3 promoter and between bp -222 and -100 of the CCL4 promoter. Because both of these elements contain CCAAT/enhancer-binding protein ß (C/EBPß) motifs, the function of C/EBPß was examined. IL-1ß stimulated the expression of C/EBPß, and the direct binding of C/EBPß to the C/EBPß motif was confirmed by EMSA and ChIP analyses. The -300 bp CCL3 promoter and -222 bp CCL4 promoter were strongly up-regulated by co-transfection with the C/EBPß expression vector. Mutation of the C/EBPß motif and reduction of C/EBPß expression by siRNA decreased the up-regulation. Additionally, another cytokine-related transcription factor, NF-κB, was also shown to be involved in the up-regulation of chemokines in response to IL-1ß, and the binding site was identified. The regulation of C/EBPß and NF-κB was confirmed by the inhibition by C/EBPß and NF-κB and by transfection with C/EBPß and NF-κB expression vectors in the presence or absence of IL-1ß. Taken together, our results suggest that C/EBPß and NF-κB are both involved in the IL-1ß-responsive up-regulation of chemokine genes in human chondrocytes. Time course experiments indicated that C/EBPß gradually and steadily induces chemokine up-regulation, whereas NF-κB activity was highest at the early stage of chemokine up-regulation.
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Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Quimiocina CCL3/biosíntesis , Quimiocina CCL4/biosíntesis , Condrocitos/metabolismo , Interleucina-1beta/metabolismo , FN-kappa B/metabolismo , Regulación hacia Arriba/fisiología , Proteína beta Potenciadora de Unión a CCAAT/genética , Células Cultivadas , Quimiocina CCL3/genética , Quimiocina CCL4/genética , Condrocitos/citología , Humanos , Interleucina-1beta/farmacología , Mutación , FN-kappa B/genética , Elementos de Respuesta/fisiología , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Osteoarthritis (OA), the most common form of arthritis, is associated with joint malfunction and chronic disability in the aged population. It is a multifactorial disorder to which several factors-such as age, sex, trauma, and obesity-contribute significantly. Obesity is one of the most influential but modifiable risk factors because it exerts an increased mechanical stress on the tibiofemoral cartilage. However, the high prevalence of OA in obese individuals in non-weightbearing areas, like finger joints, suggests that the link between being overweight and OA lies with factors other than simple biomechanics. An important correlation has been made between obesity and inflammation. Adipose tissues (and the infrapatellar fat pad) play an important role in this context because they are the major source of cytokines, chemokines, and metabolically active mediators called adipokines (or adipocytokines). These metabolic factors are known to possess catabolic and proinflammatory properties and to orchestrate the pathophysiological processes in OA. This review provides information on the relationship between obesity and OA through biomechanical and biochemical factors and highlights the functions of important obesity-related inflammatory products in the initiation and progression of OA. This information will broaden our thinking in identifying the targets for both prevention and intervention for OA.
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Mediadores de Inflamación/metabolismo , Obesidad/complicaciones , Osteoartritis/complicaciones , Adiponectina/metabolismo , Tejido Adiposo/metabolismo , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Humanos , Inflamación/complicaciones , Inflamación/fisiopatología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Leptina/metabolismo , Obesidad/fisiopatología , Osteoartritis/fisiopatología , Prevalencia , Resistina/metabolismo , Factores de Riesgo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE OF REVIEW: Osteoarthritis is a joint disease characterized by a nonsymptomatic, preradiographical phase that if distinguished would allow earlier osteoarthritis diagnosis. Biochemical biomarkers offer a potential nonradiographical alternative to detect early, nonsymptomatic osteoarthritis. RECENT FINDINGS: Biomarker development for osteoarthritis diagnosis is still in the forefront of the research repertoire in osteoarthritis. A number of previously identified biomarkers derived from cartilage breakdown or enzymes that cause cartilage degeneration still have prominence and are now better characterized with increasing use in identifying disease severity, progression, and testing treatment options. Combinations of cartilage-derived and bone-derived biomarkers have been used to subgroup osteoarthritis patients that could impact treatment and address the importance of bone turnover in cartilage integrity. Increasingly, inflammation markers have been used to profile osteoarthritis progression attesting to the inflammatory nature of osteoarthritis. The application of proteomic technologies has generated several new, nonconventional biomarkers that could allow better profiling of osteoarthritis. SUMMARY: Biomarker combinations have the ability to subgroup the heterogenous osteoarthritis population to allow a better scrutiny of diagnosis and treatment options. The application of different technological platforms to osteoarthritis would allow a better understanding of its pathology and could provide for appropriate candidates for earlier detection of osteoarthritis.
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Biomarcadores/metabolismo , Osteoartritis/diagnóstico , Osteoartritis/metabolismo , Huesos/metabolismo , Cartílago/metabolismo , Progresión de la Enfermedad , Diagnóstico Precoz , Humanos , Mediadores de Inflamación/metabolismo , ProteómicaRESUMEN
If we wish to understand whether development influences the rate or direction of morphological evolution, we must first understand the developmental bases of morphological variation within species. However, quantitative variation in adult morphology is the product of molecular and cellular processes unfolding from embryonic development through juvenile growth to maturity. The Atchley-Hall model provides a useful framework for dissecting complex morphologies into their component parts as a way of determining which developmental processes contribute to variation in adult form. We have examined differences in postnatal allometry and the patterns of genetic correlation between age-specific traits for ten recombinant inbred strains of mice generated from an intercross of LG/J and SM/J. Long bone length is closely tied to body size, but variation in adult morphology is more closely tied to differences in growth rate between 3 and 5 weeks of age. These analyses show that variation generated during early development is overridden by variation generated later in life. To more precisely determine the cellular processes generating this variation we then examined the cellular dynamics of long bone growth plates at the time of maximum elongation rate differences in the parent strains. Our analyses revealed that variation in long bone length is the result of faster elongation rates of the LG/J stain. The developmental bases for these differences in growth rate involve the rate of cell division and chondrocyte hypertrophy in the growth plate.
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Desarrollo Óseo/genética , Huesos/anatomía & histología , Placa de Crecimiento/fisiología , Ratones Endogámicos/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Estudios de Cohortes , Cruzamientos Genéticos , Femenino , Variación Genética , Masculino , Ratones , Ratones Endogámicos/anatomía & histología , Ratones Endogámicos/genética , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: To elucidate the effects of resistin on human articular chondrocytes and to generate a picture of their regulation at the transcriptional and posttranscriptional levels. METHODS: Human articular chondrocytes were cultured with resistin. Changes in gene expression were analyzed at various doses and times. Cells were also treated with the transcription inhibitor actinomycin D after resistin treatment or with the NF-kappaB inhibitor IKK-NBD before resistin treatment. Gene expression was tested by quantitative real-time polymerase chain reaction. Computational analysis for transcription factor binding motifs was performed on the promoter regions of differentially expressed genes. TC-28 chondrocytes were transfected with CCL3 and CCL4 promoter constructs, pNF-kappaB reporter, and NF-kappaB and CCAAT/enhancer binding protein beta (C/EBPbeta) expression vectors with or without resistin. RESULTS: Resistin-treated human articular chondrocytes increased the expression of cytokines and chemokines. Levels of messenger RNA (mRNA) for matrix metalloproteinase 1 (MMP-1), MMP-13, and ADAMTS-4 also increased, while type II collagen alpha1 (COL2A1) and aggrecan were down-regulated. The cytokine and chemokine genes could be categorized into 3 groups according to the pattern of mRNA expression over a 24-hour time course. One pattern suggested rapid regulation by mRNA stability. The second and third patterns were consistent with transcriptional regulation. Computational analysis suggested the transcription factors NF-kappaB and C/EBPbeta were involved in the resistin-induced up-regulation. This prediction was confirmed by the cotransfection of NF-kappaB and C/EBPbeta and the IKK-NBD inhibition. CONCLUSION: Resistin has diverse effects on gene expression in human chondrocytes, affecting chemokines, cytokines, and matrix genes. Messenger RNA stabilization and transcriptional up-regulation are involved in resistin-induced gene expression in human chondrocytes.
Asunto(s)
Cartílago Articular/efectos de los fármacos , Condrocitos/efectos de los fármacos , Citocinas/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Expresión Génica/efectos de los fármacos , Resistina/farmacología , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAMTS5 , Cartílago Articular/metabolismo , Células Cultivadas , Condrocitos/metabolismo , Colágeno Tipo II/genética , Colágeno Tipo II/metabolismo , Dactinomicina/farmacología , Femenino , Humanos , Masculino , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/metabolismo , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Persona de Mediana Edad , FN-kappa B/antagonistas & inhibidores , Fragmentos de Péptidos/farmacología , Estabilidad del ARN/efectos de los fármacos , ARN Mensajero/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
Osteoarthritis (OA) is one of the most debilitating diseases affecting mankind with severe financial and emotional consequences. The heterogeneity of the human population, lack of complete understanding of the OA disease process, and the slow progressive nature of the disease characterized by prolonged periods of nonsymptomatic, degenerative changes has hampered development of ideal diagnostic and prognostic portfolios. The difficulties associated with early OA diagnosis by exclusively radiographic techniques has propelled a need to identify specific biomarkers for rapid and effective early OA diagnosis, better patient prognosis, and for monitoring the efficacy of pharmacological interventions to the disease process. This review highlights some of the biochemical biomarkers in current use in OA, their applications and limitations. Investigation of single nucleotide polymorphisms as genetic biomarkers and the application of technologies such as lipidomics and metabolomics to OA are generating potentially additional biomarkers that could be helpful for detecting early OA phenomena in humans.