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PubMed1995

Use of an in vivo model to determine the effects of interleukin-1 on cells at different stages in the osteoclast lineage.

In vitro model systems have been used extensively to study factors that affect osteoclast formation and to identify osteoclast precursors. However, in vitro systems do not examine the entire process of osteoclast differentiation simultaneously and lack accessory cells normally present in vivo. Additionally, the role that metabolism of the factor may play on its osteotropic activity in vivo is not addressed by these culture systems. Therefore, we have developed an in vivo model that permits us to examine simultaneously the effects of osteotropic factors on three distinct stages of osteoclast differentiation: (1) multipotent osteoclast precursors, the granulocyte-macrophage colony-forming unit (CFU-GM); (2) more differentiated marrow mononuclear osteoclast precursors; and (3) mature osteoclasts already present on bone surfaces. In the current study, we used interleukin-1 (IL-1) as a prototypic osteotropic factor to test the utility of this system to delineate the cellular mechanisms responsible for enhanced osteoclast activity stimulated by this cytokine. IL-1 induced hypercalcemia and enhanced the growth and differentiation of CFU-GM, increased the number of more committed mononuclear osteoclast precursors, and stimulated mature osteoclasts to resorb bone. These data demonstrate that this simple in vivo model permits the easy delineation of the stages of osteoclast development, in which osteotropic factors act to enhance bone turnover, and may be useful in understanding the mechanism of action of antiresorptive agents.

Analysis of Variance↗
PubMed1996

High extracellular calcium stimulates osteoclast-like cell formation and bone-resorbing activity in the presence of osteoblastic cells.

The present study was performed to examine the effect of the high concentration of extracellular calcium ([Ca2+]e) on osteoclast-like cell formation and bone-resorbing activity in the presence or absence of osteoblasts. High [Ca2+]e (3 and 5 mM) significantly stimulated osteoclast-like cell formation in osteoblast-containing mouse bone cell cultures, although high [Ca2+]e did not affect the formation of osteoclast-like cells from hemopoietic blast cells supported by granulocyte-macrophage colony-stimulating factor in mouse spleen cell cultures. The osteoclast-like cells, newly formed by high [Ca2+]e in the presence of osteoblasts, possessed the ability to form pits on the dentine slices. The conditioned medium from osteoblastic MC3T3-E1 cells treated with high [Ca2+]e (5 mM) significantly increased the formation of osteoclast-like cells from hemopoietic blast cells, compared with the control medium. Dantrolene, an inhibitor of calcium mobilization from the intracellular calcium pool, and indomethacin significantly blocked high [Ca2+]e-stimulated osteoclast-like cell formation in the presence of osteoblasts, although voltage-dependent calcium channel blockers and anti-insulin-like growth factor I antibody did not affect it. High [Ca2+]e, however, significantly stimulated the bone-resorbing activity of mature osteoclasts in osteoblast-containing mouse bone cell cultures, although high [Ca2+]e inhibited bone-resorbing activity in isolated rabbit osteoclasts. An increase in the extracellular magnesium concentration (5 mM) affected neither osteoclast-like cell formation nor bone-resorbing activity. In conclusion, high [Ca2+]e stimulated osteoclast-like cell formation and bone-resorbing activity of mature osteoclasts, presumably via osteoblasts.

Animals↗
PubMed2005

Human trabecular bone-derived osteoblasts support human osteoclast formation in vitro in a defined, serum-free medium.

While it has been assumed that osteoblasts in the human support osteoclast formation, in vitro evidence of this is currently lacking. We tested the ability of normal human trabecular bone-derived osteoblasts (NHBCs) to support osteoclast formation from human peripheral blood mononuclear cells (PBMC) in response to treatment with either 1alpha,25-dihydroxyvitamin D3 (1,25D) or parathyroid hormone (PTH), using a serum-replete medium previously used to support human osteoclast formation on a stroma of murine ST-2 cells. Under these conditions, NHBC did not support osteoclast formation, as assessed by morphological, histochemical, and functional criteria, despite our previous results demonstrating a link between induction of RANKL mRNA expression and NHBC phenotype in these media. We next tested a defined, serum-free medium (SDM) on NHBC phenotype, their expression of RANKL and OPG, and their ability to support osteoclast formation. SDM, containing dexamethasone (DEX) and 1,25D, induced phenotypic maturation of NHBC, based on the expression of STRO-1 and the bone/liver/kidney isoform of alkaline phosphatase (AP). PTH as a single factor did not induce phenotypic change. 1,25D and DEX induced the greatest ratio of RANKL:OPG mRNA, predictive of supporting osteoclast formation. Consistent with this, co-culture of NHBC with CD14+ PBMC, or bone marrow mononuclear cell (BMMC), or CD34+ BMMC precursors in SDM + 1,25D + DEX, resulted in functional osteoclast formation. Osteoclast formation also occurred in PTH + DEX stimulated co-cultures. Interestingly, SDM supplemented with recombinant RANKL (25-100 ng/ml) and M-CSF (25 ng/ml), did not induce osteoclast formation from any of the osteoclast precursor populations in stromal-free cultures, unlike serum-replete medium. This study demonstrates that under the appropriate conditions, adult human primary osteoblasts can support de novo osteoclast formation, and this model will enable the detailed study of the role of both cell types in this process.

ADP-ribosyl Cyclase↗
PubMed1983

Inhibition of osteoclastic motility by prostaglandins I2, E1, E2 and 6-oxo-E1.

We have recently found that calcitonin (CT), a hormone which inhibits osteoclastic bone resorption, completely abolishes the normally intense cytoplasmic motility of isolated osteoclasts. Here we report that prostaglandin (PG)I2, PGE1, PGE2 and 6-oxo-PGE1 cause an identical change in behaviour to that induced by CT. The order of potency was PGI2 greater than PGE1 greater than 6-oxo-PGE1 greater than PGE2. We found that, unlike CT which causes prolonged immotility in osteoclasts, the effect of these PGs was transient. The transient nature of the inhibition was not caused by their decay or inactivation, nor was it due to production in the cultures of a stimulator of osteoclast motility. Osteoclasts refractory to one PG were also less sensitive to the others, but showed no loss of sensitivity to CT, suggesting that the PGs share a common receptor system, distinct from that for CT. The PGs, like CT, appear to operate by increasing the cyclic AMP level in osteoclasts. The identical nature of the response of osteoclasts to PGs and CT, and the shared use of cyclic AMP as second messenger, suggest that the PGs, like CT, act directly on osteoclasts to inhibit bone resorption by these cells. Osteoblasts are known to make PGs, and we suggest that osteoblasts make them as agents of the local control of osteoclastic bone resorption. Paradoxically, when PGs are added to bone in organ culture they stimulate bone resorption. Like PTH they increase osteoblastic cyclic AMP levels, and the effect of adding PGs to bone may be a transient direct inhibition of osteoclasts followed by a sustained PTH-like stimulation of osteoclasts through osteoblasts. This mechanism may account for the bone resorption seen in inflammatory and malignant disease.

Alprostadil↗
PubMed1982

Isolation of osteoclasts from fetal rat long bones.

Cell isolates containing multinucleate osteoclasts were obtained from longitudinally split fetal rat long bones by treatment with testicular hyaluronidase. The total yield of osteoclasts and the osteoclast enrichment of the isolate were increased if the intact bones were first cultured for 72 h. Even greater enhancement was obtained if the bones were treated with 1,25-dihydroxycholecalciferol [1,25(OH)2D3] during the culture period. This technique resulted in a cell population containing approximately 15% osteoclasts in yields greater than 50 osteoclasts per long bone. The yield of osteoclasts and the percentage of osteoclasts correlated well with the extent of bone resorption induced by 1,25(OH)2D3. The effectiveness of several isolation procedures was compared using the 1,25(OH)2D3-treated long bones. Conventional digestion with 1 mg/ml crude collagenase gave a much poorer yield of osteoclasts than simply agitating the split long bones. Hyaluronidase plus EDTA was not significantly different from EDTA alone. Even with milder procedures, however, the isolated osteoclasts were damaged as judged by their failure to exclude trypan blue. The osteoclasts are obviously very fragile cells. The isolation technique coupled with May-Grunwald-Giemsa staining permitted reliable determination of the median number of nuclei per osteoclast. This parameter was the same in uncultured bones or in bones cultured for 72 h in control media. Treatment with 1,25(OH)2D3 increased the nuclear number. At lower levels of bone resorption, nuclear number did not increase, but it was significantly greater in more highly resorbed bones.

Animals↗
PubMed2000

Prostaglandin E2 directly inhibits bone-resorbing activity of isolated mature osteoclasts mainly through the EP4 receptor.

Prostaglandins (PGs) are well known to be important local factors in regulating bone formation and resorption. PGE2 is a potent stimulator of bone resorption because of enhancing osteoclast formation by its indirect action through stromal cells. However, the direct action of PGE2 on functionally mature osteoclasts is still controversial. In this study using highly purified rabbit mature osteoclasts, we examined the direct effect of PGE2 on osteoclastic bone-resorbing activity and its mechanism. PGE2 inhibited resorption pit formation on a dentine slice by the purified osteoclasts in a dose- and time-dependent manner. The inhibitory effect appeared as early as 4 hours after the PGE2 addition. Forskolin and 12-0-tetradecanoyl phorbol-13-acetate (TPA), respective activators of adenylate cyclase and protein kinase C, also decreased the osteoclastic bone-resorbing activity. PGE2 increased the content of intracellular cAMP in a dose range effective for the inhibition of bone resorption, whereas the prostanoid did not alter the intracellular level of inositol triphosphate. The inhibition of osteoclastic bone resorption by PGE2 was amplified and diminished by a cAMP phosphodiesterase inhibitor (isobutyl methylxanthine) and a protein kinase A inhibitor (Rp-cAMP), respectively. Of four different subtypes of PGE2 receptors (EPs), EP4 mRNA was predominantly expressed in isolated osteoclasts, whereas the other types of EP mRNA were detected in only small amounts. These results suggest that the PGE2 inhibitory effect was mediated by an adenylate cyclase system coupled with EP4. This possible association of PGE2 with EP4 in mature osteoclasts was supported by the finding that a specific agonist of EP4 (AE-604) inhibited the bone-resorbing activity and elevated the intracellular cAMP content. However, butaprost, a selective EP2 agonist, also mimicked the PGE2 effects on isolated osteoclasts although EP2 mRNA expression was minimal. In conclusion, PGE2 directly inhibits bone-resorbing activity of functionally mature osteoclasts by activation of the adenylate cyclase system, perhaps mainly through EP4.

Adenylyl Cyclases↗
PubMed1998

Phorbol myristate acetate downregulates the binding sites for colony-stimulating factor-1 on osteoclasts isolated from rats.

Colony-stimulating factor-1 (CSF-1) is the growth factor for the cells of the mononuclear phagocytic system and for osteoclasts. We tested whether phorbol myristate acetate (PMA), a phorbol ester activating protein kinase C, modulates the number of binding sites for CSF-1 on isolated rat osteoclasts. PMA decreased binding of CSF-1 to osteoclasts within 60 minutes. The effect of PMA was dose dependent at concentrations between 10(-9) M and 10(-6) M. The inactive phorbol ester, 4alpha-phorbol 12,13-didecanoate, had only a slight effect. Since the osteoclast preparation was contaminated with other cells, the action of PMA on the osteoclasts might have been either direct or indirect. In pure osteoclasts harvested by a micropipette, the downregulation of CSF-1 binding by PMA reached only about three-quarters of that in nonpurified preparations. Addition of osteoblastic osteosarcoma UMR106 cells increased the effect of PMA. Antiserum against CSF-1, which was added to osteoclasts contaminated with other cells, mainly osteoblasts, partially inhibited the effect of PMA, but the antiserum had no effect in pure osteoclasts. These data suggest that the effect mediated by osteoblasts or other contaminating cells is due to the release of CSF-1, which is known to downregulate its binding sites on osteoclasts. The direct action of PMA on osteoclasts decreased the binding only to about 40%, in contrast to CSF-1 which completely downregulated the binding. The data also differ from the published results about macrophages. In these cells, PMA downregulates the binding of CSF-1 completely. The CSF-1 binding sites on osteoclasts recovered within 4 hours after removal of PMA, and cycloheximide, an inhibitor of protein synthesis, inhibited the recovery.

Animals↗
PubMed1991

Arg-Gly-Asp (RGD) peptides and the anti-vitronectin receptor antibody 23C6 inhibit dentine resorption and cell spreading by osteoclasts.

Studies with a range of monoclonal and polyclonal antisera to components of the human, rat, and chick vitronectin receptor, alpha V beta 3, and the VLA beta 1 chain show that chick and rat osteoclasts express similar integrin receptors to those described in man. Biochemical analysis with monoclonal antibody 23C6 confirmed the presence on chick osteoclasts of a vitronectin receptor heterodimer of similar size (110/95 kDa reduced) to that immunoprecipitated from human osteoclastoma giant cells. The synthetic peptide GRGDSP, corresponding to the cell adhesion sequence in fibronectin, but not GRGESP peptide, induced significant (P less than 0.005) osteoclast retraction in chick and rat osteoclasts at IC50s (+/- SEM) of 210.0 +/- 14.4 and 191.4 +/- 13.7 microM, respectively; monoclonal anti-vitronectin receptor alpha V beta 3 complex antibody, 23C6, produced similar changes in chick osteoclasts (IC50 = 1.45 +/- 0.22 microM). Antibody 23C6 inhibited the number of pits resorbed in dentine by chick osteoclasts over a concentration range of 4.4 to 88 micrograms/ml; a significant 76% reduction (P = 0.03) was observed at a final concentration of 88 micrograms/ml (6 microM). The effect of peptides upon dentine resorption was less dramatic. No consistent inhibition was seen using chick osteoclasts. Inhibitory effects on resorption by rat osteoclasts were, however, observed; significant reduction in resorption occurred with both GRGDSP (78%; P less than 0.01) and GRGESP (67%; P = 0.02) peptides at 400 microM peptide concentration. These data demonstrate that osteoclast function can be disrupted by low concentrations of the anti-vitronectin receptor antibody, 23C6. The inhibitory effects of the peptides used in this study produced effects on dentine resorption which were generally weaker and variable, although osteoclast cell adhesion was consistently inhibited in an Arg-Gly-Asp (RGD)-dependent manner. We conclude that the vitronectin receptor may play an important role in effecting resorption of mineralized tissues by osteoclasts.

Amino Acid Sequence↗
PubMed1989

Dichloromethylenebisphosphonate (Cl2MBP) inhibits bone resorption through injury to osteoclasts that resorb Cl2MBP-coated bone.

Dichloromethylenebisphosphonate (Cl2MBP, formerly Cl2MDP) inhibits bone resorption in vivo and in vitro. The mechanism by which it inhibits osteoclastic bone resorption has not been established. To investigate this, osteoclasts were isolated from rat long bone and incubated with Cl2MBP (10(-9)-10(-5) M) on bone slices. Bone resorption was assessed as plan area resorbed after 6 and 24 h by scanning electron microscopy. Although Cl2MBP inhibited bone resorption in the first 6 h of culture, inhibition was more marked in the incubation period between 6 and 24 h. This pattern of accelerating inhibition is unlike the pattern we have observed using other resorption-inhibitors, and suggested resorption-mediated osteoclast injury. In keeping with this, we found reduced numbers of osteoclasts, and morphological features of cell injury and degeneration of osteoclasts, after incubation with Cl2MBP on bone slices. Bone seemed to be an essential component in Cl2MBP-mediated injury, since osteoclast numbers and morphology on plastic coverslips were unaffected by the bisphosphonate. Moreover, bone slices preincubated with Cl2MBP showed similar effects on resorption and morphology to cultures in in which osteoclasts on bone were continuously immersed in Cl2MBP. Neither non-resorptive cells (macrophages, UMR 106 cells), nor osteoclasts prevented from resorption by calcitonin, showed evidence of cytotoxicity after incubation on bone slices with Cl2MBP. These results suggest that even relatively high concentrations of Cl2MBP in the fluid phase do not affect osteoclasts, nor does contact with Cl2MBP-coated bone surfaces, but that injury to osteoclasts, and a consequent reduction in bone resorption, occurs when osteoclasts excavate bone surfaces upon which Cl2MBP is adsorbed.

Animals↗
PubMed1989

Prostaglandin E2 initially inhibits and then stimulates bone resorption in isolated rabbit osteoclast cultures.

Osteoclasts were isolated from the long bones of neonatal rabbits and cultured on devitalized bovine bone slices for 8, 24, 48 and 72 h with and without prostaglandin E2 (PGE2) (10(-6) M). The number of osteoclasts present at the end of the culture periods was counted after staining the cells for tartrate resistant acid phosphatase (TRAP). After removal of the cells, the resorption lacunae excavated by the osteoclasts were observed by scanning electron microscopy (SEM) and their size and depth calculated by computer-assisted morphometric and stereomorphometric techniques. PGE2 had no effect on the number of TRAP positive multinucleated osteoclasts, but decreased the number of TRAP positive mononuclear cells. The total area of the excavated pits and the area excavated per osteoclast in PGE2-treated cultures were decreased by 62 and 58% respectively after 8 h in culture. After 24 h in culture, the total excavated area and the excavated area per osteoclast were still 44 and 38% lower in the PGE2-treated cultures than in the corresponding control cultures. However, after 48 h of culture, resorptive activity in PGE2-treated cultures was consistently greater than in control cultures. In the course of a 48 h culture period, the PGE2 concentration decreased from 1.0 x 10(-6) to 0.3 x 10(-6) M. Thus, despite the continuous presence of PGE2, the resorptive activity of osteoclasts not only recovered from the transient inhibitory effect of PGE2, but was actually greater than in the control cultures. This confirms that the effects of PGE2 in isolated osteoclast preparations are inhibitory in short term cultures, but shows that the effects of PGE2 in such preparations are stimulatory in longer term cultures. Proliferating stromal cells with osteoblast-like characteristics comprised approximately 45% of the 'osteoclast' cultures at the start of the cultures, but their number increased to 93% of the total cell population at 48 h and to 98% at 72 h. Our results suggest that the PGE2-induced stimulation of osteoclastic activity represents an indirect effect mediated by stromal cells derived from bone marrow. Our results also indicate that the increased resorptive activity in PGE2 treated cultures can be accounted for by an increase in the size of the resorption lacunae and is not caused by an increase in osteoclast number.

Acid Phosphatase↗
PubMed1995

Differential effects of transforming growth factor-beta on osteoclast-like cell formation in mouse marrow culture: relation to the effect of zinc-chelating dipeptides.

The effect of transforming growth factor-beta (TGF-beta) on osteoclast-like cell formation in mouse marrow culture in vitro was investigated. The bone marrow cells were cultured for 7 days in alpha-minimal essential medium containing a well-known bone resorbing agent. Osteoclast-like cell formation was estimated with staining for tartrate-resistant acid phosphatase (TRACP), a marker enzyme of osteoclasts. The presence of TGF-beta (10(-13)-10(-11) M) caused a significant increase in the number of osteoclast-like multinucleated cells (MNCs); the maximum effect was seen with 10(-12) MTGF-beta. With a higher concentration (10(-10) M) of TGF-beta, the growth factor dramatically inhibited the 1,25-dihydroxyvitamin D5 [1,25(OH)2D3; 10(-8) M]-induced formation of osteoclast-like MNCs. This inhibitory effect was also seen in the formation of osteoclast-like MNCs stimulated by parathyroid hormone (10(-8) M), prostaglandine E2 (10(-6) M), and interleukin-1 alpha (50 U/ml). The stimulatory effect of TGF-beta (10(-12) M) on osteoclast-like MNCs formation was inhibited by zinc sulfate (10(-6) M) or zinc-chelating dipeptide [beta-alanyl-L-histidinato zinc (AHZ), 10(-6) M]. The stimulating effect of TGF-beta was markedly weakened by the presence of EGTA (0.5 mM), a chelator of Ca2+. The inhibitory effect of zinc compounds was not seen in the presence of EGTA. Moreover, the inhibitory effect of TGF-beta (10(-10) M), zinc sulfate (10(-6) M), or AHZ (10(-6) M) on osteoclast-like MNCs formation was not demonstrated in mature osteoclastic cells, although calcitonin (3 x 10(-8) M) significantly inhibited the osteoclastic formation. The present study demonstrates that TGF-beta has a stimulating and an inhibiting effect on osteoclast-like cell formation in mouse marrow culture, and that zinc can inhibit the stimulatory effect of TGF-beta.

Animals↗
PubMed1990

The effects of stimulators of intracellular cyclic AMP on rat and chick osteoclasts in vitro: validation of a simplified light microscope assay of bone resorption.

The aim of this study was to investigate whether a cyclic AMP-mediated inhibitory mechanism is present in embryonic chick osteoclasts and to extend data implicating cyclic AMP in the inhibition of neonatal rat osteoclasts. Dibutyryl cyclic AMP ((Bu)2cAMP) (5 x 10(-4) M and above) and isobutylmethylxanthine (IBMX) (10(-4) M and above) reduced the number of pits made in slices of devitalized bovine cortical bone by chick osteoclasts over 24 h. The effect of forskolin (FSK) on chick osteoclasts was biphasic, 10(-5) M producing a weak and variable reduction in pit number while 10(-6) M and 10(-7) M stimulated resorption. Doses of FSK (10(-5) M) and (Bu)2cAMP (3 x 10(-4) M), which individually produced no consistent significant effect, produced a synergistic and highly significant reduction in pit number when used in combination, implying that these agents were acting through a common mechanism, presumably cyclic AMP. Stimulatory doses of FSK were associated with increased osteoclast numbers, implicating cyclic AMP in the formation of osteoclasts. In comparative experiments using neonatal rat osteoclasts, (Bu)2cAMP (10(-4) M and above), IBMX (10(-3) M) and FSK (10(-7) M and above) all reduced the number of pits excavated. Strongly inhibitory doses of these agents caused contraction of chick osteoclasts into a hemispherical shape; contraction of rat osteoclasts into a stellate shape occurred with (Bu)2cAMP and FSK, but not with IBMX. Our results implicate cyclic AMP in the inhibition of both rat and chick osteoclasts, and show that pit counting in the light microscope is a valid method of analyzing the disaggregated osteoclast resorption assay.

1-Methyl-3-isobutylxanthine↗
PubMed1995

Osteoclast function in Paget's disease and multiple myeloma.

Paget's disease of bone and multiple myeloma are characterized by increased numbers of osteoclasts and markedly increased bone resorption at the sites of the disease. In Paget's disease the osteoclasts are abnormal morphologically and contain viral-like nuclear inclusions, but in multiple myeloma the osteoclasts are normal. The bone lesions in both Paget's disease and multiple myeloma appear to be due to local stimulation of osteoclast formation and bone resorption. In situ hybridization techniques, bone marrow cultures, and cytokine assays have been used to examine osteoclast function in Paget's disease and multiple myeloma. Interleukin-6 (IL-6) has been implicated as a potential mediator for the increased osteoclast activity in both diseases. In Paget's disease, IL-6 is produced by the osteoclasts, the osteoclasts express IL-6 receptors and IL-6 mRNA, and increased levels of IL-6 are present in the marrow plasma and serum of these patients. Similarly, increased levels of IL-6 have been detected in sera from some patients with multiple myeloma. Multiple myeloma cells do not produce IL-6 in vivo but marrow stromal cells or the osteoclasts may be the source of IL-6 in multiple myeloma. IL-6 is a growth factor for multiple myeloma cells, and treating patients with anti-IL-6 decreases the tumor burden in some patients. Thus, IL-6 may be an autocrine/paracrine factor in both Paget's disease and in multiple myeloma. Multiple myeloma cells also produce osteoclast activating factors (OAFs) that can stimulate osteoclast formation and activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Marrow↗
PubMed1995

Modulation of osteoclast differentiation by local factors.

Bone-resorbing osteoclasts are of hemopoietic cell origin, probably of the CFU-M-derived monocyte-macrophage family. Bone marrow-derived osteoblastic stromal cells play an important role in modulating the differentiation of osteoclast progenitors in two different ways: one is the production of soluble factors, and the other is cell-to-cell recognition between osteoclast progenitors and osteoblastic stromal cells. M-CSF is probably the most important soluble factor, which appears to be necessary for not only proliferation of osteoclast progenitors, but also differentiation into mature osteoclasts and their survival. A number of local factors as well as systemic hormones induce osteoclast differentiation. They are classified into three categories in terms of the signal transduction: vitamin D receptor-mediated signals [1 alpha,25(OH)2D3]; protein kinase A-mediated signals (PTH, PTHrP, PGE2, and IL-1); and gp130-mediated signals (IL-6, IL-11, oncostatin M, and leukemia inhibitory factor). All of these osteoclast-inducing factors appear to act on osteoblastic cells to commonly induce osteoclast differentiation factor (ODF), which recognizes osteoclast progenitors and prepares them to differentiate into mature osteoclasts. This line of approach will undoubtedly produce new ways to treat several metabolic bone diseases caused by abnormal osteoclast recruitment such as osteoporosis, osteopetrosis, Paget's disease, rheumatoid arthritis, and periodontal disease.

Animals↗
PubMed2004

Glow discharge plasma pretreatment enhances osteoclast differentiation and survival on titanium plates.

Despite the fact that several reports have demonstrated osteoclast activity on various bioactive ceramics, osteoclast functions on surface-modified titanium have not come under focus. This study aimed to examine whether the increasing surface energy of glow discharge plasma (GDP) involved in protein adhesion containing the RGD (Arg-Gly-Asp) sequence affects osteoclast responses on titanium plates. We examined osteoclast differentiation and survival rates on titanium plates with and without GDP. The amounts of osteoclasts on titanium plates were not increased by GDP after 1 week. However, osteoclast differentiation was greatly activated by GDP pretreatment, as tartrate-resistant acid phosphatase synthesis significantly increased on the titanium plates with GDP. Additionally, since the presence of osteoclasts was detected only on the titanium plates with GDP, even after 4h cultivation in a coculture test, the osteoclasts survival rate was increased by GDP pretreatment. As osteoclast responses were affected even on surface modified metallic materials, we concluded that novel approaches are needed not only for osteoclastic resorption on ceramic materials but also for osteoclast responses on surface-modified metallic materials.

Acid Phosphatase↗
PubMedDate not supplied

Histomorphometric and biochemical study of osteoclasts at orthodontic compression sites in the rat during indomethacin inhibition.

Prostaglandins affect the number of osteoclasts at compression sites in orthodontic tooth movement. They may also have a role in tooth movement and influence the extent of root resorption. The purpose was to examine the effect of indomethacin on the activity of resident osteoclasts, recruitment of new osteoclasts and root resorption at orthodontic compression sites. Two separate populations of osteoclasts were studied: those resident at the sites after initial appliance activation and those recruited by a subsequent activation. Orthodontic appliances were activated to provide mesially directed forces of 40 g on the maxillary molars of rats. The appliances were activated with the same force after 4 days. The rats were killed at 1, 3, 6 and 10 days after initial activation. Half of the rats were injected with indomethacin. Tooth movement was measured cephalometrically; osteoclast numbers, sizes, numbers of nuclei per osteoclast and root resorption were assessed histomorphometrically; tartrate-resistant acid phosphatase (TRAP) in alveolar bone was measured biochemically. Indomethacin inhibited both initial tooth displacement and that following the delay. It also reduced the increase in osteoclast numbers, total osteoclast surface and alveolar bone TRAP at day 10. It had no effect on the surface area of each individual osteoclast or number of nuclei in each osteoclast. Root resorption increased in both groups but it was enhanced at day 10 in the indomethacin group. These data suggest that orthodontic tooth movement after appliance activation requires the recruitment of osteoclasts to sites of compression and that this is indomethacin-sensitive. Furthermore, indomethacin enhances root resorption at compression sites 10 days after appliance reactivation.

Acid Phosphatase↗
PubMed1999

Regulation of osteoclast activity.

Osteoclasts are the primary cell type responsible for bone resorption. This paper reviews many of the known regulators of osteoclast activity, including hormones, cytokines, ions, and arachidonic acid metabolites. Most of the hormones and cytokines that inhibit osteoclast activity act directly on the osteoclasts. In contrast, most of the hormones and cytokines that stimulate osteoclast activity act indirectly through osteoblasts. Particularly interesting in this regard are agents that directly inhibit activity of highly purified osteoclasts yet stimulate activity of osteoclasts that are co-cultured with osteoblasts. Recent studies have demonstrated that the primary mechanism by which bone resorptive agents stimulate osteoclast activity indirectly is likely to be up-regulation of production of osteoclast differentiation factor/osteoprotegerin ligand (ODF/OPGL) by the osteoblasts. In addition to discussing regulators of osteoclast activity per se, this paper also reviews the role of osteoclast apoptosis to limit the extent of bone resorption.

Animals↗
PubMed2003

Involvement of capacitive calcium entry and calcium store refilling in osteoclastic survival and bone resorption process.

Bone resorption is closely dependent on osteoclastic survival and osteoclast apoptotic cell death could represent a key step at the end of this process. In order to precise the possible role of calcium movement in osteoclastic cell death, we investigated whether intracellular calcium store replenishment and capacitive calcium entry (CCE) are involved in osteoclastic survival and bone resorption. We demonstrate that (i). thapsigargin, a sarco-endoplasmic reticulum calcium ATPase pump (SERCA) blocker, decreases both osteoclastic survival and bone resorption process, (ii). 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365, two store-operated channel (SOC) blockers, dramatically decrease osteoclastic survival and bone resorption and (iii). culture in calcium-free medium and thapsigargin exposure synergically inhibit osteoclastic survival which falls dramatically to a value close to 0% (P<0.001). Inversely, osteoclastic survival increases significantly when thapsigargin-treated cells are cultured in the presence of 20mM calcium, suggesting that increasing extracellular calcium concentration stimulates osteoclasts survival when the filling of intracellular stores is prevented. Taken together, our data strongly suggest that in osteoclasts, calcium movements between cellular compartments involved in the regulation of calcium signalling, such as calcium stores refilling and CCE, are closely associated to the regulation of osteoclast survival and bone resorption.

Animals↗