RESUMO
The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene.
Assuntos
Condrócitos , Modelos Animais de Doenças , Osteocondroma , Receptores do Ácido Retinoico , Receptor gama de Ácido Retinoico , Animais , Camundongos , Receptores do Ácido Retinoico/agonistas , Receptores do Ácido Retinoico/metabolismo , Osteocondroma/tratamento farmacológico , Osteocondroma/patologia , Osteocondroma/metabolismo , Condrócitos/metabolismo , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Fator de Transcrição STAT3/metabolismo , Proliferação de Células/efeitos dos fármacos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Neoplasias Ósseas/metabolismo , MasculinoRESUMO
When compared to general population, patients with rheumatoid arthritis are at higher risk of some malignancies (especially lymphomas and lung cancer). Genetic predisposition, chronic inflammatory stimuli and viral infections are some of the reasons untreated patients are at higher risk. Clinical studies and national/international registries collect the data about the malignancies with higher incidence (such as lung, skin and breast cancer) but on the other hand, malignancies with lower incidence (such as sarcomas) are rarely reported. We report a case of a 47-year-old male with a history of a malignant intracranial chondrosarcoma/osteochondroma who developed seropositive rheumatoid arthritis. Due to progression of erosions, the patient was initialy treated with conventional synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) and later on with rituximab. The patient's rheumatoid arthritis went and remained in remission on maintenance therapy with rituximab (every 6-8 months) and low-dose methotrexate with no relapse of malignant intracranial chondrosarcoma/osteochondroma. Rituximab should be considered as a treatment option in patients with rare and agressive malignancies, such as sarcomas.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Neoplasias Encefálicas/tratamento farmacológico , Condrossarcoma/tratamento farmacológico , Osteocondroma/tratamento farmacológico , Rituximab/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Indução de RemissãoRESUMO
Osteochondromas are cartilage-capped growths located proximate to the physis that can cause skeletal deformities, pain, limited motion, and neurovascular impingement. Previous studies have demonstrated retinoic acid receptor gamma (RARγ) agonists to inhibit ectopic endochondral ossification, therefore we hypothesize that RARγ agonists can target on established osteochondromas. The purpose of this study was to examine the action of RARγ agonist in human osteochondromas. Osteochondroma specimens were obtained during surgery, subjected to explant culture and were treated with RARγ agonists or vehicles. Gene expression analysis confirmed the up-regulation of RARγ target genes in the explants treated with NRX 204647 and Palovarotene and revealed strong inhibition of cartilage matrix and increased extracellular matrix proteases gene expression. In addition, immunohistochemical staining for the neoepitope of protease-cleaved aggrecan indicated that RARγ agonist treatment stimulated cartilage matrix degradation. Interestingly, cell survival studies demonstrated that RARγ agonist treatment stimulated cell death. Moreover, RNA sequencing analysis indicates changes in multiple molecular pathways due to RARγ agonists treatment, showing similarly to human growth plate chondrocytes. Together, these findings suggest that RARγ agonist may exert anti-tumor function on osteochondromas by inhibiting matrix synthesis, promoting cartilage matrix degradation and stimulating cell death.
Assuntos
Neoplasias Ósseas/metabolismo , Osteocondroma/metabolismo , Receptores do Ácido Retinoico/agonistas , Animais , Biomarcadores , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/etiologia , Neoplasias Ósseas/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Biologia Computacional/métodos , Perfilação da Expressão Gênica , Ontologia Genética , Lâmina de Crescimento/metabolismo , Lâmina de Crescimento/patologia , Humanos , Anotação de Sequência Molecular , Osteocondroma/tratamento farmacológico , Osteocondroma/etiologia , Osteocondroma/patologia , Transdução de Sinais , Técnicas de Cultura de Tecidos , Transcriptoma , Receptor gama de Ácido RetinoicoRESUMO
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by debilitating heterotopic ossification (HO). The retinoic acid receptor gamma agonist, palovarotene, and antibody-mediated activin A blockade have entered human clinical trials, but how these therapeutic modalities affect the behavior of pathogenic fibro/adipogenic progenitors (FAPs) is unclear. Using live-animal luminescence imaging, we show that transplanted pathogenic FAPs undergo rapid initial expansion, with peak number strongly correlating with HO severity. Palovarotene significantly reduced expansion of pathogenic FAPs, but was less effective than activin A inhibition, which restored wild-type population growth dynamics to FAPs. Palovarotene pretreatment did not reduce FAPs' skeletogenic potential, indicating that efficacy requires chronic administration. Although palovarotene inhibited chondrogenic differentiation in vitro and reduced HO in juvenile FOP mice, daily dosing resulted in aggressive synovial joint overgrowth and long bone growth plate ablation. These results highlight the challenge of inhibiting pathological bone formation prior to skeletal maturation.
Assuntos
Osso e Ossos/patologia , Miosite Ossificante/tratamento farmacológico , Ossificação Heterotópica/tratamento farmacológico , Pirazóis/efeitos adversos , Pirazóis/uso terapêutico , Estilbenos/efeitos adversos , Estilbenos/uso terapêutico , Receptores de Ativinas Tipo I , Ativinas , Animais , Diferenciação Celular , Condrogênese , Articulações/patologia , Medições Luminescentes , Camundongos , Osteocondroma/tratamento farmacológico , Osteogênese , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Análise de SobrevidaRESUMO
BACKGROUND: Dedifferentiated chondrosarcomas that arise in osteochondromas are extremely rare lesions for which very little information on treatment and outcome is available in the literature. The purpose of the present study was to describe the specific clinical, radiographic, and histologic features of this lesion and to evaluate the oncologic outcome after different treatment strategies. METHODS: We reviewed the files of the Rizzoli Institute between 1970 and 2002 and identified eighteen patients for whom adequate records and histologic images were available and in whom a high-grade sarcoma had been diagnosed at the same location as a preexisting osteochondroma. Radiographic studies, histologic slides, and clinical records were reviewed, the features of those studies were tabulated, and prognostic features and the results of treatment were identified. RESULTS: The patients included twelve men and six women with an average age of forty-six years (range, twenty-two to seventy-four years). Eight lesions occurred in patients with multiple osteochondromas, and ten occurred in patients with solitary lesions. The most common locations were the pelvis (six lesions) and the femur (five lesions). Symptoms included pain, swelling, and a growing mass; the average duration of symptoms was eighteen months. Radiographically, ten lesions appeared as a conventional secondary chondrosarcoma arising in an exostosis, whereas eight showed typical signs of dedifferentiation. Histologic evaluation of the cartilage component demonstrated thirteen grade-1 and two grade-2 chondrosarcomas. In three cases, no cartilage component was recognized. The dedifferentiated component was considered to be an osteosarcoma in nine cases (including six cases in which it was osteoblastic and three in which it was fibroblastic), a malignant fibrous histiocytoma in eight, and a fibrosarcoma in one. The dedifferentiated component represented an average of 59% (range, 20% to 100%) of the lesion. For the fifteen patients who were managed at the authors' institution, the two and five-year survival rates were 47% and 29%, respectively; the median survival time was fourteen months. Patients who were managed with a combination of surgery and chemotherapy had a better overall survival rate than did those who were managed with surgery alone (p = 0.03). CONCLUSIONS: Dedifferentiated chondrosarcoma arising in a preexisting osteochondroma is an extremely rare lesion with a poor prognosis. In the present small series, overall survival was better when wide surgical resection was combined with adjuvant chemotherapy.
Assuntos
Neoplasias Ósseas/patologia , Condrossarcoma/patologia , Osteocondroma/patologia , Adulto , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/cirurgia , Diferenciação Celular , Condrossarcoma/tratamento farmacológico , Condrossarcoma/mortalidade , Condrossarcoma/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteocondroma/tratamento farmacológico , Osteocondroma/cirurgiaRESUMO
A 5-year-old Arabian stallion with moderate effusion in the right carpal canal and intermittent lameness in this limb was diagnosed to have an osteochondroma projecting from the distal portion of the radius into the carpal canal. oral phenylbutazone treatment over the next 3 years allowed the stallion to continue its show career. Right forelimb lameness returned at that time, and ultrasonography revealed the osteochondroma impinging on the dorsal surface of the deep digital flexor tendon. The owner elected to have the osteochondroma surgically removed. The horse was anesthetized, and the carpal sheath was distended with balanced polyionic solution. A 4-mm arthroscope was inserted into the carpal sheath, and the osteochondroma projecting into the sheath was identified. The osteochondroma was removed by use of a Ferris-Smith bone rongeur, which was inserted into the carpal sheath through a stab incision over the osteochondroma. The effusion in the carpal sheath and the lameness resolved by 2 months, and the horse was returned to training 4 months after surgery.