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PubMed1997

Temporal expression of PDGF receptors and PDGF regulatory effects on osteoblastic cells in mineralizing cultures.

Platelet-derived growth factor (PDGF) is mitogenic and chemotactic for osteoblastic cells in vitro. It is expressed during osseous wound healing and stimulates formation of new bone in vivo. PDGF stimulates cells by binding to specific cell surface receptors. The purpose of this study was to examine the effects of PDGF on osteoblastic proliferation and differentiation in long-term mineralizing cultures. Utilizing Northern blot analysis, we found that continuous PDGF treatment increased histone expression, indicative of enhanced proliferation, but suppressed osteoblast differentiation, demonstrated by inhibition of alkaline phosphatase, type I collagen, and osteocalcin expression. The inhibitory effect of PDGF on the differentiated function of osteoblasts was further established by findings that PDGF significantly inhibited nodule formation. The expression of PDGF receptors varied at different stages of culture. PDGF receptor mRNA expression increased when the cells had achieved a mature phenotype, during the stage of matrix maturation, and then decreased. However, as demonstrated by thymidine incorporation assays, the capacity of PDGF to stimulate DNA synthesis actually decreased during osteoblast maturation, as receptor expression increased. To investigate this apparent contradiction, tyrosyl phosphorylation and immunoblot assays were performed to assess changes in PDGF activation of their cognate receptors. The pattern of PDGF-induced tyrosyl phosphorylation remained relatively constant. This suggests that the diminished mitogenic activity of PDGF that occurs after osteoblast differentiation is regulated at a postreceptor level.

Animals↗

PubMed1998

Intrinsic mineralization defect in Hyp mouse osteoblasts.

X-linked hypophosphatemia (XLH) is caused by inactivating mutations of PEX, an endopeptidase of uncertain function. This defect is shared by Hyp mice, the murine homologue of the human disease, in which a 3' Pex deletion has been documented. In the present study, we report that immortalized osteoblasts derived from the simian virus 40 (SV40) transgenic Hyp mouse (TMOb-Hyp) have an impaired capacity to mineralize extracellular matrix in vitro. Compared with immortalized osteoblasts from the SV40 transgenic normal mouse (TMOb-Nl), osteoblast cultures from the SV40 Hyp mouse exhibit diminished 45Ca accumulation into extracellular matrix (37 +/- 6 vs. 1,484 +/- 68 counts . min-1 . microgram protein-1) and reduced formation of mineralization nodules. Moreover, in coculture experiments, we found evidence that osteoblasts from the SV40 Hyp mouse produce a diffusible factor that blocks mineralization of extracellular matrix in normal osteoblasts. Our findings indicate that abnormal PEX in osteoblasts is associated with the accumulation of a factor(s) that inhibits mineralization of extracellular matrix in vitro.

Alkaline Phosphatase↗

PubMed2001

IGF-binding protein-5 stimulates osteoblast activity and bone accretion in ovariectomized mice.

Insulin-like growth factor binding protein-5 (IGFBP-5) is an osteoblast secretory protein that becomes incorporated into the mineralized bone matrix. In osteoblast cultures, IGFBP-5 stimulates cell proliferation by an IGF-independent mechanism. To evaluate whether IGFBP-5 can stimulate osteoblast activity and enhance bone accretion in a mouse model of osteoblast insufficiency, daily subcutaneous injections of either intact [IGFBP-5 (intact)] or carboxy-truncated IGFBP-5 [IGFBP-5-(1--169)] were given to ovariectomized (OVX) mice for 8 wk. Femur and spine bone mineral density (BMD), measured every 2 wk, showed early and sustained increases in response to IGFBP-5. Bone histomorphometry of cancellous bone showed significant elevations in the bone formation rate in both the femur metaphysis [IGFBP-5- (1)] only) and spine compared with OVX controls. IGFBP-5 also stimulated osteoblast number in the femur IGFBP-5-(1--169) only) and spine. These data indicate that IGFBP-5 effectively enhances bone formation and bone accretion in OVX mice by stimulating osteoblast activity. The finding that IGFBP-5-(1--169) is bioactive in vivo indicates that the carboxy-terminal portion is not required for this bone anabolic effect.

Animals↗

PubMed2000

Osteoblast tissue-nonspecific alkaline phosphatase antagonizes and regulates PC-1.

Tissue-nonspecific alkaline phosphatase (TNAP) is essential for bone matrix mineralization, but the central mechanism for TNAP action remains undefined. We observed that ATP-dependent (45)Ca precipitation was decreased in calvarial osteoblast matrix vesicle (MV) fractions from TNAP-/- mice, a model of infantile hypophosphatasia. Because TNAP hydrolyzes the mineralization inhibitor inorganic pyrophosphate (PP(i)), we assessed phosphodiesterase nucleotide pyrophosphatase (PDNP/NTPPPH) activity, which hydrolyzes ATP to generate PP(i). Plasma cell membrane glycoprotein-1 (PC-1), but not the isozyme B10 (also called PDNP3) colocalized with TNAP in osteoblast MV fractions and pericellular matrix. PC-1 but not B10 increased MV fraction PP(i) and inhibited (45)Ca precipitation by MVs. TNAP directly antagonized inhibition by PC-1 of MV-mediated (45)Ca precipitation. Furthermore, the PP(i) content of MV fractions was greater in cultured TNAP-/- than TNAP+/+ calvarial osteoblasts. Paradoxically, transfection with wild-type TNAP significantly increased osteoblast MV fraction NTPPPH. Specific activity of NTPPPH also was twofold greater in MV fractions of osteoblasts from TNAP+/+ mice relative to TNAP-/- mice. Thus TNAP attenuates PC-1/NTPPPH-induced PP(i) generation that would otherwise inhibit MV-mediated mineralization. TNAP also paradoxically regulates PC-1 expression and NTPPPH activity in osteoblasts.

3T3 Cells↗

PubMed2002

Antigenic phenotype of cultured human osteoblast-like cells.

BACKGROUND/AIMS: Osteoblasts are classically considered to play an important role during bone tissue development, and to be involved in the formation of mineralized bone matrix. Recent reports have suggested that they can also exert some activities directly associated with the immune system (cytokine synthesis and antigen presentation). Moreover, some authors have found antigens on osteoblast-like cells normally expressed by other cells with a common origin in bone marrow. METHODS: We isolated and cultured human osteoblast-like lines and studied their antigenic phenotype with flow cytometry using monoclonal antibodies against antigens associated with hematopoietic cells. RESULTS: Cultured cells expressed CD34, but were negative for CD45. B cell antigens CD20 and CD23 and myelomonocytic antigens CD11b, CD13, and CD16 were detected. Expression of CD3, CD14, CD15 and CD68 was negative, whereas CD25 expression was positive. CD56, an antigen expressed on NK cells, was positive. These cells were CD10, CD44, CD54, CD80, CD86 and HLA-DR positive, as previously described. An antigen specific to follicular dendritic cells was also observed on cultured osteoblast-like cells. CONCLUSIONS: The antigenic phenotypes of human osteoblast-like cells and FDC are similar. These data suggest that osteoblasts may be functionally related to certain dendritic cells and may play an additional role in bone tissue to that classically assigned.

Adult↗

PubMed2005

Role of matrix Gla protein in parathyroid hormone inhibition of osteoblast mineralization.

Parathyroid hormone (PTH) exerts biphasic effects on bone, dependent on the frequency and dose of administration. The catabolic actions of PTH on bone have been associated with continuous treatment, an increase in osteoblast-mediated resorption of bone via osteoclast activation, and inhibition of osteoblast activity and mineralization. Downregulation of differentiation markers and inhibition of mineralization by PTH have been reported in primary calvarial explants and osteoblast cell lines. Using MC3T3-E1 osteoblast-like cells, we have shown that matrix Gla protein (MGP) can be induced by PTH, and that this induction may explain the PTH-mediated inhibition of osteoblast biomineralization. MGP is a known inhibitor of mineralization, and mice deficient in Mgp show severe vascular calcification and premature bone mineralization. This review discusses the role of MGP in mineralization, comparing bone and vascular mineralization. In addition to MGP, the regulation and possible role of osteopontin, another known regulator of osteoblast mineralization, in PTH-mediated regulation of bone and vascular mineralization is discussed.

Animals↗

PubMed1999

Dexamethasone enhances In vitro vascular calcification by promoting osteoblastic differentiation of vascular smooth muscle cells.

Vascular calcification is often associated with atherosclerotic lesions. Moreover, the process of atherosclerotic calcification has several features similar to the mineralization of skeletal tissue. Therefore, we hypothesized that vascular smooth muscle cells might acquire osteoblastic characteristics during the development of atherosclerotic lesions. In the present study, we investigated the effect of dexamethasone (Dex), which is well known to be a potent stimulator of osteoblastic differentiation in vitro, on vascular calcification by using an in vitro calcification model. We demonstrated that Dex increased bovine vascular smooth muscle cell (BVSMC) calcification in a dose- and time-dependent manner. Dex also enhanced several phenotypic markers of osteoblasts, such as alkaline phosphatase activity, procollagen type I carboxy-terminal peptide production, and cAMP responses to parathyroid hormone in BVSMCs. We also examined the effects of Dex on human osteoblast-like (Saos-2) cells and compared its effects on BVSMCs and Saos-2 cells. The effects of Dex on alkaline phosphatase activity and the cAMP response to parathyroid hormone in BVSMCs were less prominent than those in Saos-2 cells. Interestingly, we detected that Osf2/Cbfa1, a key transcription factor in osteoblastic differentiation, was expressed in both BVSMCs and Saos-2 cells and that Dex increased the gene expression of both transcription factors. These findings suggest that Dex may enhance osteoblastic differentiation of BVSMCs in vitro.

Alkaline Phosphatase↗

PubMed1991

Decreased DNA synthesis by cultured osteoblastic cells in eugonadal osteoporotic men with defective bone formation.

To determine the osteoblastic dysfunction that may be involved in the pathophysiology of osteoporosis in men we have compared histomorphometric indices of bone formation with in vitro characteristics of osteoblastic cells isolated from the trabecular bone surface in 23 untreated men with eugonadal osteoporosis. In most patients (n = 14), trabecular bone loss resulted from decreased bone formation evidenced by a lower than normal osteoblast surface, double tetracycline labeled surface, bone formation rate, and mean wall thickness. In these patients, DNA synthesis by cultured osteoblastic cells was altered. The peak of [3H]thymidine incorporation into DNA, the maximal DNA synthesis, and the area under the curve of cell proliferation were lower than the values in normal bone cells from age-matched controls. Parameters of bone cell growth were decreased in correlation with the extent of actively bone forming surfaces. By contrast, in patients (n = 9) with normal histomorphometric indices of bone formation, bone cell proliferation in vitro was not different from normal. Parameters of osteoblastic differentiation in vitro such as osteocalcin production and alkaline phosphatase activity were normal in the two groups of patients. This study shows that the trabecular bone loss resulting from defective bone formation in eugonadal osteoporotic men is associated with a lower than normal proliferative capacity of osteoblastic cells lining the trabecular bone surface.

Adult↗

PubMed1994

Interleukin-6 attenuates agonist-mediated calcium mobilization in murine osteoblastic cells.

Interleukin-6 (IL-6) is a multifunctional cytokine which is made by osteoblasts and has diverse effects on bone metabolism. We studied the interaction of IL-6 with the Ca2+ and cAMP signaling systems in the osteoblastic cell line UMR-106 and in primary osteoblastic cultures derived from neonatal rat calvariae. IL-6 did not alter basal intracellular calcium concentration ([Ca2+]i) but inhibited Ca2+ transients induced by parathyroid hormone (PTH), prostaglandin E2 (PGE2), and endothelin-1 in both dose- (100-400 U/ml) and time- (4-48 h) dependent manners. The effect of the cytokine was abolished by the tyrosine kinase inhibitor, herbimycin A (50 ng/ml). The IL-6 effect on the Ca2+ message system was related to suppressed production of hormonally induced inositol 1,4,5-triphosphate and inhibition of Ca2+ release from intracellular stores. Hormonally induced calcium entry pathways (estimated by using Mn2+ as a surrogate for Ca2+) were not, however, altered by the cytokine. IL-6 did not modulate cAMP generation in osteoblasts. With respect to osteoblast function, IL-6, although having no effect on cell proliferation by itself, greatly enhanced the antiproliferative effect of PGE2 and PTH. Because the production of IL-6 in osteoblasts is stimulated by calciotropic hormones (e.g., PTH and PGE2), the suppressive effect of the cytokine on hormonally induced Ca2+ transients may serve as an autocrine/paracrine mechanism for modulating the effect of hormones on bone metabolism.

Animals↗

PubMed1997

Effects of ionizing radiation on proliferation and differentiation of osteoblast-like cells.

Diagnostic radiation for immediate post-surgical assessment of osseointegrated dental implants has been discouraged, due to the possibility of detrimental effects of ionizing radiation on healing and remodeling of bone. To assess this possibility, we investigated the effects of ionizing radiation on proliferation and differentiation of osteoblasts using osteoblast-like cells isolated from the calvariae of newborn rats (ROB) and a clonal osteoblastic cell line (MC3T3-E1). The cells were exposed on day 3 to a single dose of x-rays at either 40, 100, 400, or 4000 mGy, respectively, from a linear accelerator radiotherapeutic machine (Linac) or a 40-mGy dose from a diagnostic chest x-ray machine. The effects of radiation on cell growth and alkaline-phosphatase-specific (ALP) activity were evaluated at three-day intervals after irradiation up to day 12 in ROB cells, and evaluated at day 12 in MC3T3-E1 cells. At the culture end-point, the effects on formation of bone-like nodules were also evaluated in both ROB and MC3T3-E1 cells. Exposure of 4000 mGy differentially affected the two cell types. It inhibited cell growth and alkaline phosphatase activity, and inhibited DNA content in MC3T3-E1 cells. This irradiation also strongly inhibited the formation of bone-like nodules in ROB cells. On the other hand, exposure of 40-, 100-, and 400-mGy (Linac) and 40-mGy (diagnostic quality) irradiation induced no significant changes in cell growth, alkaline phosphatase activity, and formation of bone-like nodules in ROB cells. These doses also induced no significant changes in DNA content and ALP activity in MC3T3-E1 cells. These results indicate that ionizing radiation at a single dose of up to 400 mGy induces no significant changes in cell growth and differentiation of osteoblast-like cells, at least in vitro. Higher radiation doses (4000 mGy) may exert different effects on cell proliferation and cell differentiation of osteoblasts, depending on the cell types affected. Thus, diagnostic radiation seems to have less effect on proliferation and differentiation of osteoblasts.

Alkaline Phosphatase↗

PubMed1995

Effects of the Pasteurella multocida toxin on osteoblastic cells in vitro.

Pasteurella multocida toxin induces localized osteolysis in the turbinate bones of swine. Osteolysis appears to be due to an increased level of osteoclastic bone resorption, although osteoblast activity may also be impaired. We studied the effects of purified toxin on the osteoblastic phenotype of the ROS 17/2.8 rat osteoblastic osteosarcoma cell line. Treatment of both embryonic bovine lung cells and a nonosteoblastic rat osteosarcoma cell line (ROS 25/1) with nanomolar doses of toxin produced marked cytotoxic actions. In the osteoblastic ROS 17/2.8 cells, this level of toxin reduced expression of an osteoblastic marker (alkaline phosphatase), was associated with matrix mineralization, but had no cytopathologic action. The osteoblastic cell population may be resistant to a direct cytotoxic effect but is nevertheless a target for toxin action.

Alkaline Phosphatase↗

PubMed1988

Chick osteoblasts contain fluoride-sensitive acid phosphatase activity.

We used histological and biochemical methods to determine the cellular origin of bone matrix fluoride-sensitive acid phosphatase in chicken bone. Embryonic chicken calvariae were embedded in plastic and sections stained for acid phosphatase at various concentrations of substrate and fluoride. Acid phosphatase activity was observed in osteoblasts and osteoclasts but not in fibroblasts. Striking inhibition of osteoblastic acid phosphatase occurred at 100 microM fluoride, a concentration that had no apparent effect on osteoclastic acid phosphatase. Inhibition of osteoblastic and osteoclastic acid phosphatase by fluoride was also examined using extracts of embryonic chicken calvarial cells, mouse osteoblasts (MC3T3-El cell line), and purified chick osteoclasts, respectively. Fluoride is a partial competitive inhibitor of both chicken and mouse osteoblastic acid phosphatases, with apparent inhibition constants of 10-100 microM. These concentrations of fluoride correspond to those that increase bone formation in vitro and in vivo. In contrast, the apparent inhibition constant for fluoride of osteoclastic acid phosphatase was much higher (i.e., 0.5 mM). In summary, this study demonstrates that chicken osteoblasts contain an acid phosphatase that is sensitive to inhibition by low concentrations (i.e., microM) of fluoride.

Acid Phosphatase↗

PubMed1989

Cytochemical properties of osteoblast cell membrane domains.

The interactions of osteoblasts with one another and with the extracellular milieu are of vital importance for cell function. These interactions are mediated by cell membrane-associated components. In the present work, we studied the distribution of several mediators known to be associated with the cell surface, using ultrastructural cytochemistry, to characterize the three cell membrane domains (osteoid, lateral, and vascular) of osteoblasts. Osteoblasts in neonatal rat calvariae were studied for cell surface distribution of alkaline phosphatase (APase), calcium-activated adenosine triphosphatase (Ca2+-ATPase), calcium, soybean agglutinin (SBA)-reactive sites, and peanut agglutinin (PNA)-reactive sites. APase was absent in the osteoid domain but was evenly distributed in the other domains. Ca2+-ATPase was found to be concentrated mainly in the lateral domains. In contrast, calcium was present in all cell membrane domains. Using lectins conjugated to horseradish peroxidase, we demonstrated that SBA binding sites were evenly distributed along the osteoblast cell membrane, whereas PNA binding sites were absent or minimally present in the osteoid and lateral domains but were evenly distributed in the vascular domain. These results suggest that the various functions of osteoblasts may be facilitated by specialized cell membrane domains which are cytochemically distinct. Previous reports have failed to demonstrate the cytochemical differences between the three domains of the osteoblast cell membrane.

Alkaline Phosphatase↗

PubMed2004

Modeling of phosphate ion transfer to the surface of osteoblasts under normal gravity and simulated microgravity conditions.

We have modeled the transport and accumulation of phosphate ions at the remodeling site of a trabecular bone consisting of osteoclasts and osteoblasts situated adjacent to each other in straining flows. Two such flows are considered; one corresponds to shear levels representative of trabecular bone conditions at normal gravity, the other corresponds to shear level that is representative of microgravity conditions. The latter is evaluated indirectly using a simulated microgravity environment prevailing in a rotating wall vessel bioreactor (RWV) designed by NASA. By solving the hydrodynamic equations governing the particle motion in a RWV using a direct numerical simulation (DNS) technique, the shear stress values on the surface of the microcarriers are found. In our present species transfer model, osteoclasts release phosphate ions (Pi) among other ions at bone resorption sites. Some of the ions so released are absorbed by the osteoblast, some accumulate at the osteoblast surface, and the remainder are advected away. The consumption of Pi by osteoblasts is assumed to follow Michaelis-Menten (MM) kinetics aided by a NaPi cotransporter system. MM kinetics views the NaPi cotransporter as a system for transporting extracellular Pi into the osteoblast. Our results show, for the conditions investigated here, the net accumulation of phosphate ions at the osteoblast surface under simulated microgravity conditions is higher by as much as a factor of three. Such increased accumulation may lead to enhanced apoptosis and may help explain the increased bone loss observed under microgravity conditions.

Animals↗

PubMed2004

Hypergravity stimulates osteoblast phenotype expression: a therapeutic hint for disuse bone atrophy.

Physiological actions of osteoblasts are disordered by gravity unloading. We investigated the possibility that the appropriate level of hypergravity could improve osteoblast functions that are susceptible to mechanical unloading. We evaluated hypergravity effects on the 1alpha,25-dihydroxyvitamin D(3) (VD)-inducible osteocalcin expression of primary rat osteoblasts. Cell culture plates were centrifuged for 24 h at 3, 6, 12, 24, and 48 g in a 37 degrees C incubator. The mRNA levels were analyzed by quantitative RT-PCR. The mRNA levels for osteocalcin and vitamin D receptor (VD-R) at 12 g were enhanced to 187% and 228% of the 1 g control, respectively. However, the excess hypergravity conversely decreased osteocalcin expression. Osteocalcin gene expression was enhanced by VD/VD-R through the vitamin D-responsive element in the promoter. The increased osteocalcin expression might reflect the augmented VD-R expression. Alternatively, Runx2, a master gene of osteoblast differentiation, might be responsible for the osteocalcin induction, since the Runx2 mRNA levels were also increased to 247% of control at 12 g. Another VD-inducible osteoblast phenotype, alkaline phosphatase, was also upregulated at 12 g and 24 g. The appropriate level of hypergravity enhanced the VD-inducible expression of osteocalcin, a typical phenotype of osteoblast differentiation. These data suggest molecular features to prevent disuse bone atrophy of long-term bed-rest patients.

Animals↗

PubMed2005

Bone morphogenetic protein regulation of early osteoblast genes in human marrow stromal cells is mediated by extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling.

Bone marrow stromal cells (MSC) are the major source of osteoblasts for bone remodeling and repair in postnatal animals. Rodent MSC cultured with bone morphogenetic proteins (BMPs) differentiate into osteoblasts, but most human MSC show a poor osteogenic response to BMPs. In this study we demonstrate that BMP-induced osteogenesis in poorly responsive human MSC requires modulation of ERK and phosphatidylinositol 3-kinase (PI3-K) pathways. Either treating human MSC cultures with the MAPK/ERK kinase inhibitor PD98059 or transferring them to serum-free medium with insulin or IGF-I permits BMP-dependent increases in the expression of the early osteoblast-associated genes, alkaline phosphatase and osteopontin. Increased expression of these genes in BMP-treated, serum-free cultures correlates with increased nuclear levels of activated Smads, whereas serum-free cultures of human MSC expressing constitutively active MAPK/ERK kinase show decreased expression of early osteoblast genes and decreased nuclear translocation of BMP-activated Smads. Inhibiting ERK activity in human MSC also elevates the expression of Msx2, a transcription factor that is directly regulated by Smad-binding elements in its promoter. Therefore, growth factor stimulation leading to high levels of ERK activity in human MSC results in suppressed BMP-induced transcription of several early osteoblast genes, probably because levels of BMP-activated nuclear Smads are decreased. In contrast, inhibiting the insulin/IGF-I-activated PI3-K/AKT pathway decreases BMP-induced alkaline phosphatase and osteopontin expression in serum-free cultures of human MSC, but increases BMP activation of Smads; thus, PI3-K signaling is required for BMP-induced expression of early osteoblast genes in human MSC either downstream or independent of the BMP-activated Smad signaling pathway.

Alkaline Phosphatase↗

PubMed1989

Osteocalcin as an index of osteoblast function during and after ovine pregnancy.

Fetal and neonatal calcium requirements impose heavy demands on maternal bone and mineral homeostasis. The functional response of maternal osteoblasts to this stress is poorly understood. Therefore, plasma osteocalcin (OC) levels were measured by homologous RIA in age-matched nonpregnant, pregnant, and postpartum ewes to evaluate osteoblast function. In pregnant ewes from day 35 of gestation to term, the plasma OC level was suppressed to 8.2 +/- 0.5 micrograms/liter (mean +/- SEM; n = 36) compared with age-matched nonpregnant ewes (18.3 +/- 1.1 micrograms/liter; n = 39; P less than 0.0005). Plasma OC rose to the nonpregnant value by day 20 postpartum and was elevated above this level for the following 40 days (e.g. 44.0 +/- 5.0 micrograms/liter at 48-53 days; P less than 0.0005). The timing of changes in plasma OC levels and weaning did not correlate. The validity of plasma OC measurement as a marker of osteoblast function was assessed by determining the OC plasma production and clearance rates using an [125I]ovine OC infusion method. The OC plasma production rates in matched controls (n = 6), pregnant (n = 9), and 48-53-day postpartum sheep (n = 7) were 1.5 +/- 0.2, 0.5 +/- 0.04 (P less than 0.001 vs. control), and 3.6 +/- 0.6 mg/day (P less than 0.005 vs. pregnant sheep), respectively. In one ewe studied longitudinally, the OC plasma production rate increased by 15 days after parturition and achieved a 10-fold elevation at 49 days postpartum. The OC plasma clearance rate (3.3 +/- 0.3 liters/h) was the same in control, pregnant, and postpartum ewes. It is concluded that 1) changes in plasma OC levels during and after ovine pregnancy reflected changes in OC production, 2) plasma OC measurements are likely to be a useful index of osteoblast function in pregnancy, and 3) osteoblast function appears to be depressed during ovine pregnancy and enhanced markedly in the interval 20-60 days postpartum. The relationship between osteoblast function, as indicated by OC production, and bone formation remains to be clarified.

Aging↗

PubMed1990

Characterization of the transferrin receptor in UMR-106-01 osteoblast-like cells.

The accumulation of iron or aluminum can cause metabolic bone disease, but the mechanisms by which these agents affect bone metabolism remain uncertain. Since transferrin (Tf) can bind several different metals in plasma, equilibrium radioligand binding studies were performed to identify and characterize the Tf receptor in UMR-106-01 osteoblast-like cells; the role of Tf as a modifier of metal-induced changes in cell proliferation was also examined. Osteoblast-like cells grown in serum-free medium have approximately 40,000 Tf receptors on the cell membrane. Tf receptor expression increases during iron depletion and decreases with iron supplementation; the number of Tf receptors was also inversely related to both cell density and the rate of cell proliferation in vitro. Physiological levels of unsaturated Tf (5 microM) enhanced DNA synthesis in osteoblast-like cells maintained in serum-free medium, as measured by the incorporation of tritiated thymidine into DNA. Although neither 10 microM iron (Fe) nor 10 microM gallium (Ga), a known antiproliferative agent, altered DNA synthesis in UMR-106-01 cells during 48-h incubations in serum-free medium, both agents reduced the rate of DNA synthesis when added to serum-free medium containing 5 microM apo-Tf. Decreases in the incorporation of [3H] thymidine into DNA were also noted in osteoblast-like cells incubated for 48 h with 3 microM partially saturated iron Tf or gallium Tf. The results indicate that osteoblast-like cells have a single class of membrane receptors for Tf and that the regulation of Tf receptor expression in UMR-106-01 cells is similar to that in other cell types. The uptake of iron and gallium via the Tf-receptor complex can affect osteoblast proliferation, and such a mechanism may contribute to the bone cell toxicity of various metals.

Acetates↗