ABSTRACT
Letrozole is a reversible nonsteroidal aromatase inhibitor that is widely used in postmenopausal breast cancer patients. It is well established that letrozole decreases bone density owing to estrogen depletion; however, few studies have reported its direct effect on bone cells in vitro. Therefore, we investigated the effect of letrozole on bone metabolism, focusing on osteoclastogenesis. Letrozole did not affect the viability, proliferation, or migration of bone marrow-derived macrophages (BMMs); however, it reduced the multinucleation of immature osteoclasts and subsequent bone resorption in vitro. Overall, letrozole inhibited the expression of dendritic cell-specific transmembrane protein (DC-STAMP), tartrate-resistant acid phosphatase, calcitonin receptor, and cathepsin K. Among them, the reduced expression of DC-STAMP was the most prominent. However, this downregulation of DC-STAMP expression following letrozole treatment was not related to the inhibition of major osteoclastogenesis pathways, such as the nuclear factor-κB (NF-κB), c-Fos, and nuclear factor of activated T cell c1 (NFATc1) pathways, but was attributed to the inhibition of p38, which is known to reside upstream of DC-STAMP expression. Notably, the anti-osteoclastogenic effect of letrozole was abolished following treatment with the p38 activator anisomycin. Contrary to our expectations, these results strongly suggest a previously unknown anti-osteoclastogenic activity of letrozole, mediated by the downregulation of the p38/DC-STAMP pathway.
Subject(s)
Dendritic Cells/drug effects , Letrozole/pharmacology , Membrane Proteins/metabolism , Osteoclasts/drug effects , Signal Transduction/drug effects , p38 Mitogen-Activated Protein Kinases/metabolism , Animals , Bone Resorption/drug therapy , Bone Resorption/metabolism , Cell Differentiation/drug effects , Cell Fusion/methods , Cell Proliferation/drug effects , Dendritic Cells/metabolism , Down-Regulation/drug effects , Macrophages/drug effects , Macrophages/metabolism , Mice , Mice, Inbred ICR , NF-kappa B/metabolism , NFATC Transcription Factors/metabolism , Osteoclasts/metabolism , Osteogenesis/drug effects , Proto-Oncogene Proteins c-fos/metabolismABSTRACT
Hypoxia suppresses osteoblastic differentiation and the bone-forming capacity. As the leading osteoinductive growth factor used clinically in bone-related regenerative medicine, recombinant human bone morphogenic protein-2 (rhBMP-2) has yielded promising results in unfavorable hypoxic clinical situations. Although many studies have examined the effects of rhBMP-2 on osteoblastic differentiation, mineralization and the related signaling pathways, those of rhBMP-2 on osteoblastic cells remain unknown, particularly under hypoxic conditions. Therefore, this study was conducted under a 1% oxygen tension to examine the differentiating effects of rhBMP-2 on osteoblastic cells under hypoxia. rhBMP-2 could also induce the differentiation and mineralization of Osteoblastic (MC3T3-E1) cells under 1% hypoxic conditions. rhBMP-2 could also induce the differentiation and mineralization of MC3T3-E1 cells under 1% hypoxic conditions. rhBMP-2 increased the alkaline phosphatase {ALP} activity in a time dependent manner, and expression of ALP, collagen type-1 (Col-1) and osteocalcin (OC) mRNA were up-regulated significantly in a time- and concentration-dependent manner. In addition, the area of the mineralized nodules increased gradually in a concentration-dependent manner. Western blot analysis, which was performed to identify the signaling pathways underlying rhBMP-2-induced osteoblastic differentiation under hypoxic conditions, showed that rhBMP-2 significantly promoted the phosphorylation of the p38 mitogen-activated protein kinase (MAPK) in a time-dependent manner. A pretreatment with SB203580, a p38 MAPK inhibitor, inhibited the rhBMP-2-mediated differentiation and mineralization. Moreover, the phosphorylation of p38 induced by rhBMP-2 was inhibited in response to a pretreatment of the cells with Go6976, a protein kinase D {PKD) inhibitor. These findings suggest that rhBMP-2 induces the differentiation and mineralization of MC3T3-E1 cells under hypoxic conditions via activation of the PKD and p38 MAPK signaling pathways.
ABSTRACT
Hemifacial microsomia (HFM) is the most common craniofacial anomaly after cleft lip and cleft palate; this deformity primarily involves the facial skeleton and ear, with either underdevelopment or absence of both components. In patients with HFM, the management of the asymmetries requires a series of treatment phases that focus on their interception and correction, such as distraction osteogenesis or functional appliance treatment during growth and presurgical orthodontic treatment followed by mandibular and maxillary surgery. Satisfactory results were obtained in a 9-year-old girl with HFM who was treated with distraction osteogenesis. At the age of 19, genioplasty and mandible body augmentation with a porous polyethylene implant (PPE, Medpor®, Porex) was sequentially performed for the functional and esthetic reconstruction of the face. We report a case of HFM with a review of the literature.
