RESUMEN
Owing to the central role of osteoclasts in bone physiology and remodeling, manipulation of their maturation process provides a potential therapeutic strategy for treating bone diseases. To investigate this, we genetically inhibited the Notch signaling pathway in the myeloid lineage, which includes osteoclast precursors, using a dominant negative form of MAML (dnMAML) that inhibits the transcriptional complex required for downstream Notch signaling. Osteoclasts derived from dnMAML mice showed no significant differences in early osteoclastic gene expression compared to the wild type. Further, these demonstrated significantly lowered resorption activity using bone surfaces while retaining their osteoblast stimulating ability using ex vivo techniques. Using in vivo approaches, we detected significantly higher bone formation rates and osteoblast gene expression in dnMAML cohorts. Further, these mice exhibited increased bone/tissue mineral density compared to wild type and larger bony calluses in later stages of fracture healing. These observations suggest that therapeutic suppression of osteoclast Notch signaling could reduce, but not eliminate, osteoclastic resorption without suppression of restorative bone remodeling and, therefore, presents a balanced paradigm for increasing bone formation, regeneration, and healing. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2089-2103, 2019.
Asunto(s)
Regeneración Ósea , Osteoclastos/metabolismo , Osteogénesis , Receptores Notch/metabolismo , Transducción de Señal , Animales , Remodelación Ósea , Resorción Ósea , Callo Óseo/metabolismo , Linaje de la Célula , Femenino , Curación de Fractura , Genotipo , Heterocigoto , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/metabolismo , Osteoblastos/metabolismo , Fenotipo , Estrés Mecánico , Factores de Transcripción/metabolismoRESUMEN
Geriatric fractures take longer to heal and heal with more complications than those of younger patients; however, the mechanistic basis for this difference in healing is not well understood. To improve this understanding, we investigated cell and molecular differences in fracture healing between 5-month-old (young adult) and 25-month-old (geriatric) mice healing utilizing high-throughput analysis of gene expression. Mice underwent bilateral tibial fractures and fracture calluses were harvested at 5, 10, and 20 days post-fracture (DPF) for analysis. Global gene expression analysis was performed using Affymetrix MoGene 1.0 ST microarrays. After normalization, data were compared using ANOVA and evaluated using Principal Component Analysis (PCA), CTen, heatmap, and Incromaps analysis. PCA and cross-sectional heatmap analysis demonstrated that DPF followed by age had pronounced effects on changes in gene expression. Both un-fractured and 20 DPF aged mice showed increased expression of immune-associated genes (CXCL8, CCL8, and CCL5) and at 10 DPF, aged mice showed increased expression of matrix-associated genes, (Matn1, Ucma, Scube1, Col9a1, and Col9a3). Cten analysis suggested an enrichment of CD8+ cells and macrophages in old mice relative to young adult mice and, conversely, a greater prevalence of mast cells in young adult mice relative to old. Finally, consistent with the PCA data, the classic bone healing pathways of BMP, Indian Hedgehog, Notch and Wnt clustered according to the time post-fracture first and age second. CLINICAL SIGNIFICANCE: Greater understanding of age-dependent molecular changes with healing will help form a mechanistic basis for therapies to improve patient outcomes. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:149-158, 2018.
Asunto(s)
Callo Óseo/patología , Curación de Fractura , Inflamación/etiología , Factores de Edad , Animales , Proliferación Celular , Ratones , Ratones Endogámicos C57BL , Análisis de Componente Principal , Transducción de Señal/fisiologíaRESUMEN
The wealth of literature documenting differences in health care utilization by race and ethnicity underscores the need to develop a system to effectively measure health care related disparities. The Centers for Medicare & Medicaid Services has taken the first steps toward detailing the quality of care for fee-for-service (FFS) Medicare beneficiaries. Using data collected for the two-period 1997-1999 on a cross-section of beneficiaries from all states and territories of the U.S., quality was measured using a set of 24 indicators of care. The results of this effort were reported in the October 4, 2000 issue of the Journal of the American Medical Association. This article reports similar measures of quality but focuses specifically on disparities in the indicators among five disadvantaged Medicare beneficiary groups: African-American, American Indian/Alaska Natives, Asian/Pacific Islanders, Hispanics, and Medicare beneficiaries enrolled in Medicaid (dually enrolled). These indicators serve as a baseline for tracking quality improvement within disadvantaged populations and evaluating the success of efforts to reduce health care disparities at the national level. The findings suggest that patterns of disparities exist in both the inpatient and outpatient settings for disadvantaged beneficiaries. Over the next decade, the composition of Medicare beneficiaries will become more diverse. This increasing diversity makes it imperative to identify and monitor the existence and extent of health care disparities. The consistent and ongoing evaluation of racial, ethnic, and socioeconomic disparities should provide an incentive to create effective preventive programs tailored to specific community needs.