montelukast and Osteoporosis

This review summarizes the highlights in the study of adult and pediatric asthma from October 2002 through October 2003. It is easiest to categorize this year's advances into physiologic, epidemiologic, therapeutic, and primarily pediatric developments. In physiology the identification of the ADAM33 gene as an asthma susceptibility gene has led to a new hypothesis concerning the pathogenesis of asthma. Understanding the integration of the upper and lower airways is likely to have important implications for patient management. Epidemiologic studies continue to show that asthma is a significant and costly disease, with medications comprising the most significant direct costs. Early intervention and improved management can significantly reduce the burden of illness. Research presented indicates there is an opportunity for allergist-immunologists to improve diagnostic and therapeutic approaches to asthma management. Our community has a strong commitment to health care quality, education, and delivery. The Journal will reflect this commitment with a new section devoted to these issues.

Topics: Acetates; ADAM Proteins; Administration, Inhalation; Adrenal Cortex Hormones; Adult; Anti-Asthmatic Agents; Asthma; Child; Cyclopropanes; Female; Humans; Male; Metalloendopeptidases; Osteoporosis; Pregnancy; Pregnancy Complications; Quinolines; Respiratory System; Sulfides; United States

Aging is associated with the development of osteoporosis, in which cellular senescence in osteoblasts plays a key role. Leukotriene D4 (LTD4), an important cysteinyl leukotriene (cysLT), is a powerful pro-inflammatory mediator formed from arachidonic acid. However, little information regarding the effects of LTD4 on the pathogenesis of osteoporosis has been reported before. In the present study, we defined the physiological roles of LTD4 in cellular senescence in osteoblasts. Our results indicate that LTD4 treatment decreased the expression of SIRT1 in a dose-dependent manner in MC3T3-E1 osteoblastic cells. Additionally, LTD4 significantly increased the expression of p53, p21 and plasminogen activator inhibitor-1 (PAI-1). LTD4 was also found to elevate the activity of β-galactosidase (SA-β-Gal) but to prevent BrdU incorporation. Our results indicate that cysteinyl leukotriene receptor 1 (cysLT1R) could be detected in MC3T3-E1 osteoblastic cells at both the mRNA and protein levels. However, cysLT2R was not expressed in these cells. Interestingly, we found that knockdown of cysLT1R or use of the selective cysLT1R antagonist montelukast abolished the LTD4-induced reduction in SIRT1 and increase in p53, p21, and PAI-1. Notably, knockdown of cysLT1R by transfection with cysLT1R siRNA or treatment with montelukast attenuated the LTD4-induced increase in SA-β-Gal activity. Our study shows for the first time that LTD4 has a significant impact on cellular senescence in osteoblasts.

Topics: Acetates; Animals; beta-Galactosidase; Cell Line; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p21; Cyclopropanes; Humans; Leukotriene D4; Mice; Osteoblasts; Osteoporosis; Plasminogen Activator Inhibitor 1; Quinolines; Receptors, Leukotriene; RNA, Small Interfering; Sirtuin 1; Sulfides; Tumor Suppressor Protein p53