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Osteoclast-like multinucleated cells were formed from mouse bone marrow mononuclear cells, and their morphology on coverslips and on calcified dentine slices was compared by means of transmission electron microscopy. Addition of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] to bone marrow cells cultured on coverslips greatly stimulated the formation of multinucleated cells within 8 days. These multinucleated cells had the cytological features of osteoclasts (abundant pleomorphic mitochondria, a large number of vacuoles and lysosomes, many stacks of Golgi membranes, and an extensive canalicular system), but they developed neither ruffled borders nor clear zones. The multinucleated cells appeared to result from direct fusion of mononuclear progenitor cells, whose structural features were similar to those of multinucleated cells. Like isolated osteoclasts, both multinucleated cells and their precursors exhibited an intense reaction for tartrate-resistant acid phosphatase (TRACP) in the cisterns of endoplasmic reticulum and lysosomes. Multinucleated cells formed from alveolar macrophages in the presence of 1 alpha,25(OH)2D3 were totally negative for TRACP reaction. When marrow cells were cultured on dentine slices in the presence of 1 alpha,25(OH)2D3, some of the multinucleated cells were located in the shallow resorption lacunae of dentine surfaces, and they developed the characteristic ruffled borders and clear zones. The narrow extracellular spaces of the ruffled borders, the adjacent pale endocytotic vacuoles, and the dark lysosomes located in the perinuclear cytoplasm of the multinucleated cells contained numerous apatite crystals delete in resorption lacunae. These results indicate that 1) the multinucleated cells formed on coverslips from mouse marrow cells treated with 1 alpha,25(OH)2D3 exhibit non-functional basic features of osteoclast morphology, and 2) differentiation of the multinucleated cells into functional osteoclasts requires some components of calcified dentine.
Anat Rec 1989 Jul
PMID:Multinucleated cells formed on calcified dentine from mouse bone marrow cells treated with 1 alpha,25-dihydroxyvitamin D3 have ruffled borders and resorb dentine. 278 22

Positive identification of osteoclast percursors has not yet been possible. The authors have, in the present report, used a model system in the rat in which it is possible to induce the formation of multinucleated osteoclasts at a predictable and reproducible site and time (Tran Van P, Vignery A, Baron R. Anat Rec 1982, 202:445-451; Cell Tissue Res 1982, 225:283-292). This system allowed the investigation of the cellular events occurring locally during the recruitment and differentiation of osteoclast precursors. Prior to the formation of multinucleated osteoclasts, mononuclear cells positive for fluoride-inhibitable nonspecific esterase and cells positive for tartrate-resistant acid phosphatase increase in number locally. Double staining procedures demonstrated the presence of both enzymes in a number of cells, thereby suggesting that they are steps in the differentiation of a single cell population. Ultrastructural studies show that lysosomal enzymes are present in every compartment of the biosynthetic pathway, in small primary lysosomes and various forms of storage granules. As these precursors arrive at the bone surface, the storage granule lysosomes are markedly depleted. It is concluded that mononuclear precursors of the osteoclast are members of the mononuclear-phagocyte lineage and differentiate early to synthesize, store, and later secrete large quantities of lysosomal enzymes. The mature osteoclast, which, as its precursor, is positive for the mononuclear-phagocyte marker enzyme nonspecific esterase, results from the fusion of these mononuclear precursors, which occurs only after their attachment to the bone surface to be resorbed.
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PMID:Kinetic and cytochemical identification of osteoclast precursors and their differentiation into multinucleated osteoclasts. 394 57

Osteoclasts and odontoclasts have been considered multinucleated giant cells which resorb hard tissue by ruffled borders. Recently, the authors reported the presence of a mononuclear osteoclast and odontoclast with a ruffled border. However, the relative frequency of such cells and the distribution of the number of nuclei including mononuclear cells in them have not been elucidated. Six human deciduous teeth were used in this study. After fixation and decalcification, tartrate-resistant acid phosphatase (TRAP) activity was detected with the azo dye method, and then TRAP-positive cells were observed on resorbing areas of teeth by light microscopy. The cells for investigation were serially sectioned by semithin sections to observe the presence of resorptive lacuna and the number of nuclei. The TRAP activity was detected in both multinucleated and mononuclear odontoclasts from serial semithin sections, and 242 TRAP-positive cells which formed lacunae on dentin were investigated to determine the frequency distribution of the number of nuclei. The mean number of nuclei per cell was 5.3, and median was 4. Only 2.9% of odontoclasts were mononucleus and 93.8% had 10 or fewer nuclei. The majority of odontoclasts forming lacunae on the dentin were cells with 10 or fewer nuclei, and mononuclear odontoclasts participated in human deciduous tooth resorption together with multinucleated ones.
Anat Rec 1997 12
PMID:Mononuclear odontoclast participation in tooth resorption: the distribution of nuclei in human odontoclasts. 941 52

Three dental hard tissues, i.e., cementum, dentin, and enamel, are resorbed by multinucleated cells referred to as "odontoclasts." These cells have morphological and functional characteristics similar to those of bone-resorbing osteoclasts. However, concerning enamel resorption, which is a process that may occur during tooth eruption, satisfactory ultrastructural data on odontoclastic resorption are still lacking. Ultrastructural and histochemical characteristics of odontoclasts resorbing enamel of human deciduous teeth prior to shedding were examined by means of light microscopy and transmission and scanning electron microscopy. Odontoclasts that that resorbed enamel were tartrate-resistant acid phosphatase (TRAP)-positive multinucleated giant cells that were essentially the same as those that resorbed dentin and cementum. Ultrastructurally, they had numerous mitochondria, lysosomes, and free polysomes in their cytoplasm. In addition, they were characteristically rich in large cytoplasmic vacuoles containing enamel crystals in the cytoplasm opposite the ruffled border. Although they extended a well-developed, ruffled border against enamel surface, a clear zone--an area typically devoid of organelles--was rarely seen in these cells. In many cases, the cells were in very close contact with the enamel surface by the peripheral part of their cytoplasm. The enamel prisms at the resorption surface contained more loosely packed and electron-lucent enamel crystals compared with those of unresorbed, intact enamel. Furthermore, numerous thin needle- or plate-like enamel crystals that were liberated from the enamel matrix were found in the extracellular channels of the ruffled border and in various-sized cytoplasmic vacuoles in their cytoplasm. The superficial layer of the enamel matrix undergoing odontoclastic resorption stained positively with toluidine blue and for TRAP activity. The results of the present study suggest that odontoclasts resorbing enamel secrete acids as well as organic components, including hydrolytic enzymes, into the resorption zone underlying their ruffled border and that they phagocytose crystals that have been liberated from the partially demineralized enamel matrix by acids, subsequently dissolving them intracellularly.
Anat Rec 1998 10
PMID:Ultrastructural features of odontoclasts that resorb enamel in human deciduous teeth prior to shedding. 977 76

For elucidation of how physiological root resorption of deciduous teeth is initiated, the cellular events that occur surrounding the root of rabbit deciduous teeth before and at the onset of physiological root resorption were observed by means of light and electron microscopy. In addition, the cytodifferentiation of odontoclasts during the initial phase of this root resorption was evaluated by histochemical staining of tartrate-resistant acid phosphatase (TRAP) activity as a marker odontoclasts and their precursors. The present investigation was focused on the physiological root resorption of the deciduous lower second molar of rabbits from Day 0-5 postnatally. At birth, the deciduous molar had not erupted yet, and no TRAP-positive cell could be found surrounding the tissue adjacent to the root of the deciduous tooth. TRAP-positive mononuclear cells were initially detected in the coronal portion of the dental follicle of the permanent tooth at Day 1 postnatally. Ultrastructurally, these mononuclear cells had moderate numbers of mitochondria and short-strand rough endoplasmic reticulum, as well as scattered free ribosomes throughout their cytoplasm. TRAP-positive mononuclear cells then appeared in the cementoblast layer immediately adjacent to the surface of the deciduous roots. These mononuclear cells projected cytoplasmic extensions between the cementoblasts and made contact with the cementum. At that time, cell-cell contact was frequently observed between these mononuclear cells and cementoblasts. During 3-5 days postnatally, the number of TRAP-positive multinucleate odontoclasts on the root surface gradually increased. They had well-developed ruffled borders and made typical resorption lacunae on the root surface of the deciduous tooth. During this early postnatal period, neither inflammatory cells nor necrotic tissue could be observed surrounding the deciduous root. This study demonstrates that the dental follicle of the permanent tooth as well as the connective tissue adjacent to the deciduous root might play important role in site- and time-specific recruitment, development, and activation of odontoclasts before and at the onset of physiological root resorption.
Anat Rec 2001 12 01
PMID:Cellular events at the onset of physiological root resorption in rabbit deciduous teeth. 1174 94

Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor (TNF) receptor superfamily that negatively regulates osteoclastogenesis. The receptor activator of the NFKB ligand (RANKL) is one of the key regulatory molecules in osteoclast formation and binds to OPG. In this study, it was suggested that OPG and RANKL are involved in alveolar bone remodeling during orthodontic tooth movement. We examined RANKL localization and osteoclast induction in periodontal tissues during experimental movement of incisors in OPG-deficient mice. To produce orthodontic force, an elastic band was inserted between the upper right and left incisors for 2 or 5 days, and the dissected maxillae were examined for cytochemical and immunocytochemical localization of tartrate-resistant acid phosphatase (TRAP), vacuolar-type H(+)-ATPase, and RANKL. Compared to wild-type OPG (+/+) littermates, TRAP-positive multinucleated cells were markedly induced in the periodontal ligament (PDL) on the compressed side and in the adjacent alveolar bone of OPG-deficient mice. These multinucleated cells exhibited intense vacuolar-type H(+)-ATPase along the ruffled border membranes. Because of accelerated osteoclastic resorption in OPG-deficient mice, alveolar bone was severely destroyed and partially perforated at 2 and 5 days after force application. In both wild-type and OPG-deficient mice, RANKL expression became stronger at 2 and 5 days after force application than before force application. There was no apparent difference in intensity of RANKL expression between OPG (+/+) littermates and OPG-deficient mice. In both wild-type and OPG-deficient mice, expression of RANKL protein was detected in osteoblasts, fibroblasts, and osteoclasts mostly located in resorption lacunae. These results suggest that during orthodontic tooth movement, RANKL and OPG in the periodontal tissues are important determinants regulating balanced alveolar bone resorption.
Anat Rec 2002 04 01
PMID:Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin-deficient mice. 1192 Mar 84

Cartilage resorption in forming primary fallow deer antlers was studied by histochemistry and electron microscopy. A high activity of tartrate-resistant acid phosphatase (TRAP), a histochemical marker of skeletal resorbing cells, was first detected in cells located in the mesenchymal tissue separating the columns of hypertrophic cartilage. No cartilage resorption was observed in this region. Intense TRAP staining occurred in large multinucleated cells (identified as inactive osteoclasts) as well as in smaller cells (regarded as mononuclear osteoclast progenitors). On the basis of these findings it was concluded that this was the region where osteoclasts differentiated from progenitor cells. Further proximally, the mineralized cartilage was eroded by active osteoclasts that were located in Howship's lacunae and exhibited an intense TRAP staining. Electron microscopy showed that the cells identified as inactive osteoclasts lacked a polarized organization. In contrast, the active osteoclasts in the zone of cartilage resorption exhibited a typical polarized organization: the nuclei congregated near the basolateral cell surface, and there was a zone of deep membrane infoldings (ruffled border) surrounded by a clear zone at the apical cell pole adjacent to the resorption surface of the mineralized cartilage. The multinucleated cartilage-resorbing cells of the forming antler thus exhibited the typical histochemical and morphological features of active mammalian osteoclasts. Low levels of TRAP activity were also observed in hypertrophic chondrocytes; however, the specificity and potential significance of this staining remain to be elucidated.
Anat Rec 2002 Sep 01
PMID:Histochemical and ultrastructural studies of cartilage resorption and acid phosphatase activity during antler growth in fallow deer (Dama dama). 1220 66

The differentiation and functions of osteoclasts (OCs) are regulated by osteoblast-derived factors. Receptor activator of NFkB ligand (RANKL) is one of the key regulatory molecules in OC formation. Osteoprotegerin (OPG) is a novel secreted member of the TNF receptor superfamily that negatively regulates osteoclastogenesis and binds to RANKL. We examined the biological actions of macrophage-colony-stimulating factor (M-CSF), RANKL, and OPG on the differentiation of OCs isolated from cocultures of mouse osteoblastic cells and bone marrow cells. Preosteoclasts (pOCs) and OCs were characterized by their ultrastructure and the expression of OC markers such as tartrate-resistant acid phosphatase (TRAP) and vacuolar-type H(+)-ATPase. pOCs formed without any additives expressed TRAP, but showed little resorptive activity on cocultured dentine slices. TRAP-positive pOCs treated with M-CSF began to fuse with each other, but lacked a ruffled border (RB) and showed almost no resorptive activity. pOCs treated with RANKL became TRAP-positive multinucleated cells, which expressed intense vacuolar-type H(+)-ATPase along the RB membranes and exhibited prominent resorptive activity. Such effects of RANKL on pOCs were completely inhibited by the addition of OPG. OPG inhibited RB formation in mature OCs and reduced their resorptive activity, and also induced apoptosis of some OCs. These results suggest that 1) RANKL induces differentiation of functional OCs from pOCs, 2) M-CSF induces macrophage-like multinucleated cells, but not OCs, 3) OPG inhibits RB formation and resorptive activity in mature OCs, 4) OPG also induces apoptosis of OCs, and 5) RANKL and OPG are, therefore, important regulators of not only the terminal differentiation of OCs but also their resorptive function.
Anat Rec 2002 Oct 01
PMID:Regulation of osteoclast differentiation and function by receptor activator of NFkB ligand and osteoprotegerin. 1222 20

We examined the effects of long-term bisphosphonate (BP, pamidronate) administration at a therapeutic dose (1.5 mg/kg/day) on the distribution, structure, and vacuolar-type H(+)-ATPase expression of osteoclasts, and the resulting trabecular bone volume and structure in ovariectomized (OVX) mature rats. Six-month-old female rats were allocated to sham-operated control, untreated-OVX, and BP-administered OVX groups. Postoperatively, BP was administered intraperitoneally once a day to OVX rats for up to 30 days. On postoperative days 14, 30, and 60, all of the rats were killed and the distal metaphyseal area of the dissected humeri was examined. Quantitative backscattered-electron image analysis revealed that the trabecular bone volume/unit medullary area in untreated OVX rats was significantly (P < 0.05) lower than that in sham-operated controls at 30 and 60 days postoperation. BP administration significantly (P < 0.05) increased trabecular bone volume at 14, 30, and 60 days postoperation in BP-administered OVX rats compared to both sham-operated and untreated OVX rats. Compared to untreated OVX rats, the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts along the bone trabeculae in BP-administered OVX rats was not significantly decreased on days 14 and 30, but was significantly decreased on day 60. Ultrastructurally, BP administration caused the disappearance of both the ruffled border (RB) and the clear zone (CZ) structures, and decreased the expression of vacuolar-type H(+)-ATPase in most osteoclasts, but did not significantly induce apoptosis of osteoclasts detected by the terminal dUTP nick end-labeling (TUNEL) method. Our results suggest that long-term BP administration significantly reduces bone and calcified cartilage resorption through impairment of the structure and bone-resorbing function of osteoclasts, and thereby effectively maintains trabecular bone volume and structure in ovariectomy-induced acute estrogen deficiency in mature rats.
Anat Rec A Discov Mol Cell Evol Biol 2003 Sep
PMID:Cellular mechanism of inhibition of osteoclastic resorption of bone and calcified cartilage by long-term pamidronate administration in ovariectomized mature rats. 1292 92

It has been clearly established that osteoclasts, which play a crucial role in bone resorption, differentiate from hematopoietic cells belonging to the monocyte/macrophage lineage in the presence of macrophage-colony stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL). We have here investigated the M-CSF- and RANKL-induced osteoclastic differentiation of two distinct clones of the murine monocytic/macrophagic RAW 264.7 cell line, known as TIB-71 and CRL-2278, the latter cell clone being defective for the expression of the inducible nitric oxide synthase isoform in response to interferon-gamma or lipopolysaccharide. CRL-2278 cells demonstrated a more rapid osteoclastic differentiation than TIB-71 cells, as documented by morphology, tartrate-resistant acid phosphatase positivity, and bone resorption activity. The enhanced osteoclastic differentiation of CRL-2278 was accompanied by a higher rate of cells in the S/G2-M phases of cell cycle as compared to TIB-71. The analysis of nitric oxide synthase (NOS) isoforms clearly demonstrated that only neuronal NOS was detectable at high levels in CRL-2278 but not in TIB cells under all tested conditions. Moreover, the broad inhibitor of NOS activity L-NAME significantly inhibited osteoclastic differentiation of CRL-2278 cells. Altogether, these results demonstrate that a basal constitutive neuronal NOS activity positively affects the RANKL/M-CSF-related osteoclastic differentiation.
Anat Rec A Discov Mol Cell Evol Biol 2005 Oct
PMID:Different levels of the neuronal nitric oxide synthase isoform modulate the rate of osteoclastic differentiation of TIB-71 and CRL-2278 RAW 264.7 murine cell clones. 1614 87


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