Osteoclasts are multinucleated cells that resorb bone. Although osteoclasts originate from the monocyte/macrophage lineage, osteoclast precursors are not well characterized in vivo. The relationship between proliferation and differentiation of osteoclast precursors is examined in this study using murine macrophage cultures treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB (RANK) ligand (RANKL). Cell cycle–arrested quiescent osteoclast precursors (QuOPs) were identified as the committed osteoclast precursors in vitro. In vivo experiments show that QuOPs survive for several weeks and differentiate into osteoclasts in response to M-CSF and RANKL. Administration of 5-fluorouracil to mice induces myelosuppression, but QuOPs survive and differentiate into osteoclasts in response to an active vitamin D3 analogue given to those mice. Mononuclear cells expressing c-Fms and RANK but not Ki67 are detected along bone surfaces in the vicinity of osteoblasts in RANKL-deficient mice. These results suggest that QuOPs preexist at the site of osteoclastogenesis and that osteoblasts are important for maintenance of QuOPs.
Human lung adenocarcinoma, the most prevalent form of lung cancer, is characterized by many molecular abnormalities. K-ras mutations are associated with the initiation of lung adenocarcinomas, but K-ras-independent mechanisms may also initiate lung tumors. Here, we find that the runt-related transcription factor Runx3 is essential for normal murine lung development and is a tumor suppressor that prevents lung adenocarcinoma. Runx3À/À mice, which die soon after birth, exhibit alveolar hyperplasia. Importantly, Runx3À/À bronchioli exhibit impaired differentiation, as evidenced by the accumulation of epithelial cells containing specific markers for both alveolar (that is SP-B) and bronchiolar (that is CC10) lineages. Runx3À/À epithelial cells also express Bmi1, which supports self-renewal of stem cells. Lung adenomas spontaneously develop in aging Runx3 þ /À mice (B18 months after birth) and invariably exhibit reduced levels of Runx3. As K-ras mutations are very rare in these adenomas, Runx3 þ /À mice provide an animal model for lung tumorigenesis that recapitulates the preneoplastic stage of human lung adenocarcinoma development, which is independent of K-Ras mutation. We conclude that Runx3 is essential for lung epithelial cell differentiation, and that downregulation of Runx3 is causally linked to the preneoplastic stage of lung adenocarcinoma.
Long-term treatment with active vitamin D [1a,25(OH) 2 D 3 ] and its derivatives is effective for increasing bone mass in patients with primary and secondary osteoporosis. Derivatives of 1a,25(OH) 2 D 3 , including eldecalcitol (ELD), exert their actions through the vitamin D receptor (VDR). ELD is more resistant to metabolic degradation than 1a,25(OH) 2 D 3 . It is reported that ELD treatment causes a net increase in bone mass by suppressing bone resorption rather than by increasing bone formation in animals and humans. VDR in bone and extraskeletal tissues regulates bone mass and secretion of osteotropic hormones. Therefore, it is unclear what types of cells expressing VDR preferentially regulate the vitamin D-induced increase in bone mass. Here, we examined the effects of 4-week treatment with ELD (50 ng/kg/day) on bone using osteoblast lineage-specific VDR conditional knockout (Ob-VDR-cKO) and osteoclastspecific VDR cKO (Ocl-VDR-cKO) male mice aged 10 weeks. Immunohistochemically, VDR in bone was detected preferentially in osteoblasts and osteocytes. Ob-VDR-cKO mice showed normal bone phenotypes, despite no appreciable immunostaining of VDR in bone. Ob-VDR-cKO mice failed to increase bone mass in response to ELD treatment. Ocl-VDR-cKO mice also exhibited normal bone phenotypes, but normally responded to ELD. ELD-induced FGF23 production in bone was regulated by VDR in osteoblast-lineage cells. These findings suggest that the vitamin D treatment-induced increase in bone mass is mediated by suppressing bone resorption through VDR in osteoblast-lineage cells.
Bisphosphonates (BPs) are potent inhibitors of osteoclastic bone resorption and widely used for the treatment of osteoporosis and metastatic bone diseases. Recently, BPs have also been shown to benefit children with primary and secondary osteoporosis, including osteogenesis imperfecta; however, their long-term safety has not been established yet. Clinical and experimental studies have demonstrated that BPs delay or inhibit tooth eruption. The failure of tooth eruption causes several dental abnormalities. In this study, to determine the effects of BPs on tooth formation, the BP zoledronic acid (ZOL) was injected into 7- and 14-day-old rats, and the development of the mandibular teeth was examined. X-ray analysis demonstrated that ZOL inhibited the eruption of both incisors and molars and their formation, especially in the molar roots. Histological examination showed that, in ZOL-treated animals, alveolar bone remained unresorbed around tooth crowns, which injured ameloblasts and enamel matrix, leading to defects of the enamel. Furthermore, haphazard proliferation of odontogenic epithelium and mesenchyme associated with primitive tooth structures, which resembles human odontomas, was induced at the basal end of incisors but not around the molars. Tooth ankylosis to alveolar bone was occasionally observed in molars. These results suggest that administration of BPs during tooth development has the potential to inhibit tooth eruption and formation and to induce several types of dental abnormalities, which may be attributed to the altered osteoclastic activities.
Although Hertwig's epithelial root sheath (HERS) performs an important function in the formation of the tooth root, the developmental mechanisms that control HERS growth and differentiation remain to be thoroughly elucidated. Bone morphogenetic protein 4 (BMP4), which is secreted by mesenchymal cells, acts on the dental epithelium as a regulator of cell differentiation during crown formation. In an effort to determine whether BMP4 specifically regulates the development of HERS in the dental epithelium, we assessed the localizations of BMP4, BMP receptor-IB (BMPR-IB), and BMPR-II during molar root formation in the mouse. HERS cells were shown to express BMPR-IB and BMPR-II. BMP4-positive cells were detected densely in the dental papillae around HERS, thereby suggesting that BMP4 participated in HERS formation. Beads soaked in BMP4, NOGGIN, or phosphate-buffered saline (PBS) were implanted into the pulp cavity under culture conditions, and the length of HERS was evaluated with regard to the proliferating cells. After 12 h, both groups exhibited a similar HERS developmental pattern, with the length and shape of HERS bearing a close resemblance to one another. However, after 48 h, the observed HERS elongation was significantly shorter in the BMP4-treated group. In addition, proliferative cell nuclear antigens were detectable only in the NOGGIN- and PBS-treated groups. These findings demonstrate that mesenchymally expressed BMP4 regulates HERS development by preventing elongation and maintaining cell proliferation. BMP4 may, therefore, prove useful as a root-formation regulatory agent in a variety of tissue-engineering applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.