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At least 1,135 records · Page 63Linked to original sources
PubMed1997

Insulin-like growth factor-I mediates osteoclast-like cell formation stimulated by parathyroid hormone.

There have been several lines of evidence that parathyroid hormone (PTH) stimulates production of insulinlike growth factor I (IGF-I) in bone and that IGF-I stimulates osteoclast formation. Thus, the present study was performed to clarify the possible role of IGF-I in PTH-stimulated osteoclastlike cell formation and the role of PTH-responsive dual signal transduction systems (cyclic [c] AMP-dependent protein kinase [PKA] and calcium/protein kinase C [PKC]) in its mechanism. Treatment with anti-IGF-I antibody (1-10 micrograms/ml) partially but significantly blocked hPTH-(1-34)-stimulated osteoclastlike cell formation in unfractionated mouse bone cell cultures, although it did not affect osteoclastlike cell formation stimulated by 1,25-dihydroxyvitamin D3. Rp-cAMP5 (10(-4) M), a direct PKA inhibitor, as well as two types of PKC inhibitors, H-7 (10 microM) and staurosporine (3 nM), and dantrolene (10(-5) M), an inhibitor of calcium mobilization from intracellular calcium stores, all significantly blocked PTH-stimulated osteoclastlike cell formation. Anti-IGF-I antibody (3 micrograms/ml) significantly blocked osteoclastlike cell formation stimulated by 10(-4) M dbcAMP, 10(-4) M Sp-cAMPS, a direct PKA activator, and 10(-5) M forskolin in mouse bone cell cultures. Dibutyryl cAMP, forskolin, and hPTH-(1-34) significantly stimulated mRNA expression of both IGF-I and IGF-binding protein 5 (IGFBP-5) in these cultures, but neither 10(-7) M PMA, a PKC activator, nor 10(-7) M A23187 did. Moreover, anti-IGF-I antibody significantly blocked osteoclastlike cell formation stimulated by the conditioned medium from MC3T3-E1 cells pretreated with 10(-8) PTH-(1-34), which induced IGF-I and IGFBP-5 mRNA expression in these cells. In conclusion, the present study indicates that IGF-I mediates osteoclastlike cell formation stimulated by PTH and that the PKA pathway is involved in its mechanism. However, IGF-I does not seem to be the sole effector molecule to be active in this system.

Animals↗
PubMed1980

Surface immunoglobulin, lectin-induced cap formation, and phagocytic function in five patients with the leukemic phase of hairy cell leukemia.

Hairy cells from 5 patients with greater than 25% hairy cells in the peripheral blood (4 had greater than 45% hairy cells and white blood cell counts (WBC) greater than 10,000/mm3) were studied for surface immunoglobulin (SIg) presence and distribution by two methods, for lectin-induced cap formation, and for phagocytosis of zymosan. Hairy cells from all 5 cases were found to have distinct monoclonal patterns, 2 Gk, 1 MDk, 1 Dk, and 1 GMDk, as well as cap formation with SIg. All 5 cases showed distinct lectin-induced cap formation in a percentage of cells similar to the percentage of hairy cells, and 2 of the 5 patients had hairy cells which phagocytosed zymosan. These findings contrasted with the malignant cells from 4 patients with CLL, which had monoclonal SIg but no SIg cap formation and no significant percentage of lectin-induced cap formation. Cells from 2 cases of T cell lymphomas had no SIg and no lectin-induced cap formation as did cells from 2 cases of non-lymphocytic leukemia. Hairy cells not only appear to have SIg cap formation similar to some B-lymphocytes, which in some patients also phagocytose zymosan, but also demonstrate strong lectin-induced cap formation.

Adult↗
PubMed2001

45S5 bioactive glass surface charge variations and the formation of a surface calcium phosphate layer in a solution containing fibronectin.

This study investigated the effect of fibronectin adsorption on surface charge variations and calcium phosphate (Ca-P) layer formation kinetics on the surface of 45S5 bioactive glass (BG). We hypothesize that the adsorption of fibronectin on BG changes the surface charge and alters the kinetics of Ca-P layer formation on the glass surface. The charge at a material's surface modulates surface chemistry, protein adsorption, and interactions with bone cells. The zeta potential of BG in a solution containing human plasma fibronectin (TE-FN) was measured as a function of time by particle electrophoresis, and Ca-P layer formation was characterized using SEM, EDXA, and FTIR. Si, Ca, and P solution concentrations also were determined. It was found that the adsorption of fibronectin reduced the initial electronegativity of the BG surface and delayed the formation of both the amorphous and the crystalline Ca-P layers. The delayed formation of these surface layers may be attributed to the competitive binding of Ca2+ ions by the fibronectin molecule. In addition, the formation of an amorphous Ca-P layer correlated with the reversal from a negatively to a positively charged surface, independent of the presence of fibronectin. The addition of a single protein (in this case fibronectin) can significantly alter material surface parameters, such as charge, and subsequently affect the formation of a surface Ca-P layer. Furthermore, the formation of an amorphous Ca-P layer is an important event in the reactions leading to bioactive behavior, and proteins such as FN are actively involved in the transformation of the surface into a Ca-P layer.

Adsorption↗
PubMed2001

Mechanical regulation of localized and appositional bone formation around bone-interfacing implants.

The local mechanical environment around bone-interfacing implants determines, in large part, whether bone formation leading to functional osseointegration will occur. Previous attempts to relate local peri-implant tissue strains to tissue formation have not accounted for implant surface geometry, which has been shown to influence early tissue healing in vivo. Furthermore, the process by which mechanically regulated peri-implant bone formation occurs has not been considered previously. In the current study, we used a unit cell approach and the finite element method to predict the local tissue strains around porous-surfaced and plasma-sprayed implants, and compared the predictions to patterns of bone formation reported in earlier in vivo experiments. Based on the finite element predictions, we determined that appositional bone formation occurred when the magnitudes of the strain components at the tissue-host bone interface were <8%. Localized, de novo bone formation occurred when the distortional tissue strains were less than approximately 3%. Based on these threshold tissue strains, we propose a mechanoregulatory model to relate local tissue strains to the process of peri-implant bone formation. The mechanoregulatory model is novel in that it predicts both appositional and localized bone formation and its predictions are dependent on implant surface geometry. The model provides initial criteria with which the osseointegration potential of bone-interfacing implants may be evaluated, particularly under conditions of immediate or early loading.

Alloys↗
PubMed2002

The role of complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) in promoting C3 fragment deposition and membrane attack complex formation on normal peripheral human B cells.

Normal human B lymphocytes are known to activate the alternative pathway (AP) of complement, leading to C3-fragment deposition and membrane attack complex (MAC) formation. The process is mediated via complement receptor type 2 (CR2, CD21), with complement receptor type 1 (CR1, CD35) playing a subsidiary role. In this study, we examine the relative contributions of CR1 and CR2 to the deposition of C3 fragments and MAC on B lymphocytes under circumstances where all complement pathways are operational. C3-fragment deposition and MAC formation were assessed on human peripheral B lymphocytes in the presence of 30% autologous serum. Blocking the CR2 ligand-binding site with monoclonal antibody (mAb) FE8 resulted in significant reduction (37.9+/-11.9%) in C3-fragment deposition, whereas MAC formation was only marginally affected (12.1+/-22.2% reduction). Blocking the CR1 binding-site resulted in significant reduction of both C3-fragment deposition (22.0+/-14.5%) and MAC formation (47.4+/-13.8%). Both the lack of CR2 influence on MAC formation and the promotion of C3-fragment deposition by CR1 are in striking contrast to the situation where only the AP is operational. The presence of erythrocytes (E) bearing CR1, however, markedly reduced both C3-fragment deposition and MAC formation. Our data suggest that C3-fragment deposition and MAC formation on B lymphocytes in vivo may involve both AP and classical pathway activation, with CR1 contributing significantly to the latter. On the other hand, the presence of extrinsic CR1, on E, may serve to limit spontaneous MAC formation and thereby ensure cell survival in the circulation.

B-Lymphocytes↗
PubMed1995

During secondary myotube formation, primary myotubes preferentially absorb new nuclei at their ends.

Developing muscles contain at least two types of myoblasts. Early myoblasts are the first myoblast to form and are the only myoblasts present during primary myotube formation. By the time secondary myotube formation begins, early myoblasts are rare and late myoblasts are common. The late myoblasts have been postulated to give rise to secondary myotubes. While this is generally accepted, it is unclear whether late myoblasts also contribute to the growth of primary myotubes. One study has produced evidence that myoblasts present during secondary myogenesis selectively fuse with each other or with secondary myotubes, but not with primary myotubes (Harris et al. [1989a] Development 107:771-784). However, the sizes of primary myotubes increase during secondary myotube formation. We have therefore re-examined the question of whether primary myotubes absorb new nuclei during secondary myotube formation. Pregnant rats were given a single intraperitoneal injection of 5 mg of 5-bromodeoxyuridine (BrdU) on one embryonic day (from E13 to E19) and their embryos removed on E20. The brominated-nuclei were labelled with an antibody to BrdU and the myotubes were marked with anti-myosin antibodies. Double labelled sections from the soleus, tibialis anterior, and extensor digitorum longus muscles were examined with a confocal microscope. The numbers and locations of labelled nuclear profiles in primary and secondary myotubes were counted and recorded. The results show: (1) that primary myotubes absorb nuclei at all stages of development, including the period of secondary myotube formation; (2) that in the early stages of secondary myotube formation, more myoblasts fuse with primary than secondary myotubes whereas this situation is reversed by the end of secondary myotube formation; and (3) that the nuclei added to primary and secondary myotubes during the early stages of their formation are located within the middle of E20 muscles. The nuclei added to growing myotubes are preferentially located at the ends of the muscles.

Animals↗
PubMed2006

Effects of a moderate-intensity static magnetic field on VEGF-A stimulated endothelial capillary tubule formation in vitro.

Effects of a moderate-intensity static magnetic field (SMF) on the early-stage development of endothelial capillary tubule formation were examined during the initial cell growth periods using co-cultured human umbilical vein endothelial cells and human diploid fibroblasts. The co-cultured cells within a well (16 mm in diameter) were exposed to SMF intensity up to 120 mT (Bmax) with the maximum spatial gradient of 21 mT/mm using a disc-shaped permanent magnet (16 mm in diameter and 2.5 mm in height) for up to 10 days. Control exposure was performed without magnet. Some vascular endothelial cells were treated with vascular endothelial growth factor (VEGF)-A (10 ng/ml) to promote the tubule formation every 2-3 days. Four experimental protocols were performed: (1) non-exposure (control); (2) SMF exposure alone; (3) non-exposure with VEGF-A; (4) SMF exposure with VEGF-A. Photomicrographs of tubule cells immunostained with an anti-platelet-endothelial cell adhesion molecule-1 (PECAM-1 [CD31[) antibody as a pan-endothelial marker, were analyzed after culture at 37 degrees C for 4, 7, and 10 days. The mean values of the area density and the length of tubules (related mainly to arteriogenesis) as well as the number of bifurcations (related mainly to angiogenesis) were determined as parameters of tubule formation and were compared between the groups. After a 10 day incubation, in the peripheral part of the culture wells, SMF alone significantly promoted the tubule formation in terms of the area density and the length of tubules, compared with control group. In the central part of the wells, however, SMF did not cause any significant changes in the parameters of tubule formation. After a 7 day incubation, VEGF-A significantly promoted all the parameters of tubule formation in any part of the wells, compared with control group. With regard to the synergistic effects of SMF and VEGF-A on tubule formation, after a 10 day incubation, SMF significantly promoted the VEGF-A-increased area density and length of tubules in the peripheral part of the wells, compared with the VEGF-A treatment alone. However, SMF did not induce any significant changes in the VEGF-A-increased number of bifurcations in any part of the wells. The tubule cells observed in the wells had elongated, spindle-like shapes, and the direction of cell elongation was random, irrespective of the presence and direction of SMF. These findings suggest that the application of SMF to intact or VEGF-A-stimulated vascular endothelial cells leads mainly to promote or enhance arteriogenesis in the peripheral part of the wells, where the spatial gradient increases relative to the central part. The effects of SMF on the VEGF-A-enhanced tubule formation appear to be synergistic or additive in arteriogenesis but not in angiogenesis.

Angiogenesis Inducing Agents↗
PubMed2002

Role of VEGF family members and receptors in coronary vessel formation.

The specific roles of vascular endothelial growth factor (VEGF) family members and their receptors (VEGFRs) in coronary vessel formation were studied. By using the quail heart explant model, we found that neutralizing antibodies to VEGF-B or VEGF-C inhibited tube formation on the collagen gel more than anti-VEGF-A. Soluble VEGFR-1, a receptor for VEGF-A and -B, inhibited tube formation by 87%, a finding consistent with that of VEGF-B inhibition. In contrast, addition of soluble VEGFR-2, a receptor for VEGF family members A, C, D, and E, inhibited tube formation by only 43%. Acidic FGF-induced tube formation dependency on VEGF was demonstrated by the attenuating effect of a soluble VEGFR-1 and -2 chimera. The localization of VEGF R-2 and R-3 was demonstrated by in situ hybridization of serial sections, which documented marked accumulations of transcripts for both receptors at the base of the truncus arteriosus coinciding with the temporal and spatial formation of the coronary arteries by means of ingrowth of capillary plexuses. This finding suggests that both VEGFR-2 and R-3 may play a role in the formation of the coronary artery roots. In summary, these experiments document a role for multiple members of the VEGF family and their receptors in formation of the coronary vascular bed.

Animals↗
PubMed2002

Human declarative memory formation: segregating rhinal and hippocampal contributions.

The medial temporal lobe (MTL) is the core structure of the declarative memory system, but which specific operation is performed by anatomically defined MTL substructures? One hypothesis proposes that the hippocampus carries out an exclusively mnemonic operation during declarative memory formation that is insensitive to content, whereas the rhinal cortex carries out an operation supporting memory formation indirectly. To explore the interaction between a salient item feature and memory formation, we contrasted neural correlates of memory formation of high- and low-frequency words. Event-related potentials (ERPs) were recorded via depth electrodes from within the MTL in nine epilepsy patients while they memorized single words. To assess memory formation, ERPs to words subsequently recalled in a free recall test were contrasted with ERPs to forgotten words. More high- than low-frequency words were remembered. High-frequency words led to distinct ERP subsequent memory effects in rhinal cortex and hippocampus. Low-frequency words, however, were only associated with the hippocampal ERP effect. The anatomically restricted interaction between word frequency and memory formation might indicate a semantically affected operation in the parahippocampal region supporting memory formation indirectly. By contrast, the missing interaction in hippocampal recordings might suggest a direct correlate of declarative memory formation that is insensitive to item properties.

Adult↗
PubMed2004

Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor.

Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA-MB-231, MDA-MB-435 and MCF-7, induce OCL formation using a murine osteoblast-spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT-15; a human lung cancer cell line, HT-1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non-breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL-6, IL-11 and TNF-alpha. The effect of BCCM on OCL formation in osteoblast-spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL-11 or the murine IL-11 receptor; neutralising antibodies to human IL-6, IL-11 or TNF-alpha were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL-11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL-11 was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE(2) apparently enhanced OCL formation by downregulating GM-CSF production by spleen cells since recombinant murine GM-CSF inhibited OCL formation and a neutralising antibody to murine GM-CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by stimulating osteoblastic production of IL-11. The subsequent release of PGE(2) followed by inhibition of GM-CSF production by cells within the bone microenvironment plays an important part in mediating the effects of breast cancer cells on OCL formation and their resorptive activity.

Animals↗
PubMed1988

Elements required for transcription initiation of the human U2 snRNA gene coincide with elements required for snRNA 3' end formation.

Formation of the human U1 and U2 snRNA 3' ends requires both a conserved sequence, the 3' box, located downstream of the snRNA termini and sequences within the snRNA promoter regions. Indeed, replacement of the U1 snRNA promoter by mRNA promoters inhibits U1 3' end formation. We have now mutated the 5' flanking region of the human U2 gene and assayed the effects on initiation of transcription and 3' end formation. The 5' flanking region of the U2 gene contains two major promoter elements, a previously characterized distal element that enhances the efficiency of transcription and a proximal element, which our analysis localizes between positions -59 and -43 in a segment conserved in vertebrate snRNA genes. The 5' flanking region does not contain an element required solely for 3' end formation. However, when enhancer elements from an mRNA-encoding gene are introduced into a U2 promoter lacking its distal element, 3' end formation is inhibited. Together, these results suggest that the U2 promoter elements themselves are involved in 3' end formation, presumably by directing the formation of a unique transcription complex which is compatible with 3' end formation at the 3' box. Alteration of the composition of this transcription complex results in increased read-through at the 3' box.

DNA Mutational Analysis↗
PubMed1992

Theoretical analysis on cell size distribution and kinetics of foreign-body giant cell formation in vivo on polyurethane elastomers.

The nature of in vivo leukocyte adhesion and foreign-body giant cell (FBGC) formation on polyurethanes was studied through theoretical and statistical analyses in terms of cell size distribution, density changes, and kinetics of FBGC formation. The results showed that the size distribution of FBGCs followed a "most probable" distribution. During FBGC formation, the densities of FBGCs changed with time. At an early stage, the number of FBGCs increased with time to a maximum at the expense of macrophages. As more FBGCs were formed and less macrophages were present, the fusion of FBGCs among themselves became significant. This, in turn, caused a gradual decrease of FBGC density with time. The rate of FBGC formation was characterized by a rate constant that represented certain characteristics of cell fusion and FBGC formation and the density of initial FBGC-forming macrophages that were a small fraction of leukocytes adhering to the surface. The direct correlations of surface cracking and pitting and adherent FBGCs demonstrated the influence of phagocytic actions of FBGCs on the biostability of implanted polyurethanes. While the cracking was thought to be caused by oxidative degradation facilitated by oxygen ion/radical release of FBGCs, the pitting appeared to result from the Methacrol 2138F aggregates diffusing out of the polymer in an acidic microenvironment under FBGCs, which in turn could be enhanced by the surface degradation and cell phagocytosis. The added Santowhite powder in polyurethane had a significant influence on FBGC formation: It reduced FBGC density and rate of FBGC formation by reducing leukocyte adhesion and the number of macrophages participating in FBGC formation.

Amines↗
PubMed2006

Formation of hydroxyapatite-polyphosphazene polymer composites at physiologic temperature.

Aspects of the formation of bone analog composites at 37 degrees C are described. The composites are composed of hydroxyapatite (HAp) and the calcium salt of a biocompatible polymer and are capable of forming under in vivo conditions. Composite formation involves the formation of monolithic HAp from particulate calcium phosphate precursors while Ca ions liberated to the aqueous medium in which this reaction is occurring form crosslinks with the acidic polymer. The reactants are poly[bis(carboxylatophenoxy)phosphazene] (acid-PCPP), tetracalcium phosphate [Ca4(PO4)2O, TetCP], and anhydrous dicalcium phosphate (CaHPO4, DCPA). The effects of the proportion of polymer (5, 10, or 15 wt %) on the kinetics of HAp formation were studied. Compositional evolution of the solid calcium phosphates present was followed by X-ray diffraction and infrared spectroscopy analyses. HAp formation through a dissolution-precipitation process provided a mildly alkaline medium suitable for deprotonation of the acid-PCPP and for the formation of the calcium crosslinks, as monitored by infrared spectroscopy. Concurrence of crosslinking of the polymer and HAp formation was established, indicating true composite formation can be realized at physiologic temperature.

Biocompatible Materials↗
PubMed2007

S. epidermidis biofilm formation: effects of biomaterial surface chemistry and serum proteins.

Most infections due to implanted cardiovascular biomaterials are initiated by bacterial adhesion of Staphylococcus epidermidis, followed by colonization and biofilm formation on the surface of the implant. This study examined the role of serum proteins and material surface chemistry in the formation of S. epidermidis biofilm on polyurethanes (Elasthane 80A, hydrophobic) modified with polyethylene oxide (Elasthane 80A-6PEO, hydrophilic) and fluorocarbon (Elasthane 80A-6F, hydrophobic). Initial adhesion, aggregation, biofilm thickness, viability, and slime formation of S. epidermidis strain, RP62A in phosphate buffered saline (PBS), tryptic soy broth (TBS), and 20% pooled human serum was quantified. In the presence of adsorbed serum proteins, initial bacterial adhesion was suppressed significantly to <2% relative to adhesion in TSB or PBS. However, adhesion, aggregation, and proliferation increased dramatically in the 12-24 h period on Elasthane 80A and Elasthane 80A-6F, which resulted in an extensive network of biofilm. A contrasting trend was observed on the hydrophilic Elasthane 80A-6PEO surface, with minimal bacterial adhesion, which decreased steadily over 24 h. In the presence of serum proteins, an increasingly thick ( approximately 20 mum) biofilm formed on the hydrophobic surfaces over 48 h whereas the formation of a mature biofilm on the hydrophilic surface was impeded with few viable bacteria present over 48 h. Furthermore, slime was detected during the initial phase of bacterial adhesion at 2 h and increased over time with the formation of biofilm. These results have shown that while initial S. epidermidis adhesion is suppressed in the presence of adsorbed proteins, inter-bacterial adhesion possibly aided by slime production leads to the formation of a robust mature biofilm. Also, biomaterial surface chemistry affected biofilm formation and, most notably, polyethylene oxide significantly inhibited S. epidermidis biofilm formation over 48 h in vitro.

Bacterial Adhesion↗
PubMed1987

Procollagen type I carboxy-terminal extension peptide in serum as a marker of collagen biosynthesis in bone. Correlation with Iliac bone formation rates and comparison with total alkaline phosphatase.

We measured iliac bone formation rates on all surfaces after double tetracycline labeling, serum levels of type 1 procollagen carboxy-terminal extension peptide (pColl-I-C), and serum levels of total alkaline phosphatase activity (TAP) in four normal subjects and in 44 patients with various forms of metabolic bone disease. In three patients with enzymatic evidence of liver disease both biochemical serum markers were disproportionately raised. In a patient with idiopathic axial osteosclerosis serum pColl-I-C was selectively increased by more than ten-fold. In the remaining 44 subjects pColl-I-C and TAP levels correlated significantly with each other (r = 0.70) and both showed the same directional changes and broadly similar correlations with iliac bone formation rate expressed in different ways. In general, pColl-I-C levels correlated better with cancellous bone formation rates and TAP levels cortical bone formation rates. There was a modest improvement in prediction of bone formation rate with multiple regression using both markers. In 15 patients with typical uncomplicated postmenopausal osteoporosis, neither biochemical marker, singly or jointly, correlated significantly with any expression of bone formation rate. Disadvantages to the use of pColl-I-C as a marker include a significant contribution to the serum level from type 1 collagen biosynthesis in tissues other than bone, and (probably) variable metabolic clearance. For both biochemical markers the most consistently high correlations (r = 0.77-0.79) were found with total bone formation rate for the entire biopsy core volume, which is the best estimate available from a biopsy of formation rate at the bone organ level of organization in vivo. The core volume as a referent also allows the amount of bone formed on cortical, endocortical, and cancellous surfaces to be compared. Measurement of serum pColl-I-C levels merits further study as a noninvasive index of bone metabolism. Differences between normal and abnormal subjects in the relationships between a variety of biochemical markers and a variety of histologic indices have the potential for providing insight into the pathogenesis of osteoporosis.

Adolescent↗
PubMed1989

Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro.

Interleukin-1 (IL-1) alpha and beta and tumor necrosis factor (TNF) alpha and beta are potent stimulators of bone resorption in vitro and in vivo. However, the mechanisms underlying this increased bone resorption have not been clearly defined. Increased bone resorption can result from increased activity of individual osteoclasts, increased numbers of osteoclasts, or both. Therefore, we have used a long-term human marrow culture system that forms multinucleated cells (MNC) with the characteristics of osteoclasts to examine the effects of IL-1 and TNF on osteoclast formation. Human recombinant IL-1 alpha and IL-1 beta, and human recombinant TNF-alpha and TNF-beta stimulated MNC formation from 4- to 60-fold. IL-1 alpha, IL-1 beta, TNF-alpha, and TNF-beta significantly increased MNC formation at very low concentrations: 2.5 x 10(-13) M for IL-1 alpha and IL-1 beta, 10(-11) M for TNF-alpha, and 10(-10) M for TNF-beta In addition, these cytokines enhanced MNC formation in the presence of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], a potent osteotropic factor that stimulates MNC formation by stimulating fusion of mononuclear precursor cells. Simultaneous addition of IL-1 and TNF to the cultures resulted in a synergistic stimulation of MNC formation. These results suggest that: (1) IL-1 and TNF stimulate bone resorption in part by increasing osteoclast formation and (2) an extremely low concentration of these factors can synergistically increase osteoclast formation in the absence of other factors, such as 1,25-(OH)2D3. These data suggest that synergistic interactions among cytokines play an important role in maintaining bone cell activity in normal and pathologic states.

Bone Resorption↗
PubMed1992

Stimulation of bone formation in osteoporosis patients treated with fluoride associated with increased DNA synthesis by osteoblastic cells in vitro.

In this study we evaluated whether the fluoride-induced increased bone formation in osteoporosis is mediated by stimulation of bone cell proliferation and/or differentiation. We analyzed the kinetics of DNA synthesis and the phenotypic features of osteoblastic cells isolated from the trabecular bone surface in relationship to histomorphometric indices of bone formation evaluated on the same bone biopsy in 12 osteoporotic patients treated with fluoride. Osteoblastic cells isolated from patients with a higher than normal bone formation rate, increased mean wall thickness of trabecular bone packets, and high trabecular bone volume after fluoride therapy displayed a higher than normal rate of DNA synthesis in vitro. The peak of [3H]thymidine incorporation into DNA, the maximal DNA synthesis, and the area under the growth curve of osteoblastic cells isolated from these patients were higher than the values in normal bone cells obtained from age-matched controls. By contrast, in vitro parameters of osteoblastic cell proliferation were not different from normal in fluoride-treated osteoporosis patients in whom bone formation was not increased, although the duration of treatment and bone fluoride content were not different. Parameters of bone cell proliferation in vitro were increased in correlation with the mean wall thickness, and the latter correlated with the trabecular bone volume, indicating that the augmentation of bone formation and bone volume induced by fluoride was paralleled by an increased proliferation of osteoblastic cells. Basal osteocalcin production (corrected for cell protein) and alkaline phosphatase activity in vitro were comparable, and the response to 1,25-dihydroxyvitamin D3 (10 nmol/liter, 48 h) was not different in normal osteoblastic cells and in cells from fluoride-treated osteoporosis patients whether they had high or normal bone formation. The results show that the fluoride-induced increased bone formation in osteoporotic patients is associated with an increased in vitro proliferative capacity of osteoblastic cells lining the trabecular bone surface, whereas parameters of osteoblast differentiation are not affected. The data also suggest that induction of a higher than normal bone cell proliferation is prerequisite for the stimulation of bone formation by fluoride.

Aged↗
PubMed1995

Microcallus formations of the cancellous bone: a quantitative analysis of the human spine.

Microcallus formations are demonstrable in nearly all spongy bone by means of suitable preparation techniques. Histologically, these structures are immature fibrous bone. Their genesis, frequency, and importance are largely unknown. To address these issues, 26 normal human spines, 11 osteoporotic spines, and different parts of the skeleton (femur head, iliac crest) were investigated for microcallus using a new preparation technique--allowing a combined 2- and 3-dimensional analysis. According to our analysis, microcallus formation occurs frequently in persons older than 45 years of age. These formations are mainly localized in the lower thoracic and lumbar spine and are obviously more frequent in females than in males. In individuals with a trabecular bone volume (BV/TV) in the spine below 11%, microcallus formations occur regularly. But the number of microcallus formations depends more on the microarchitecture of the cancellous bone (trabecular bone pattern factor, TBPf), than on individual trabecular parameters (trabecular number, TbN; trabecular bone volume, BV/TV; and trabecular thickness, TbTh). In about 33% of cases microfractures are demonstrable in the center of the microcallus formation. It is unclear whether microcallus may be the result of a nontraumatic process. In therapy studies the bone mass could be misrepresented due to the amount of microcallus. Although it indicates instability of the bone structure, microcallus formation is not only a negative mechanism, but stabilizes and regenerates the bone tissue. Furthermore, complete new trabeculae can be formed due to bridges of microcallus between the remnant trabeculae. Osteoporosis is not the result of an inability to form microcallus formations.

Adolescent↗