scholarly journals Pregnancy-Associated Plasma Protein-A Increases Osteoblast Proliferation in Vitro and Bone Formation in Vivo

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5653-5661 ◽  
Author(s):  
Xuezhong Qin ◽  
Jon E. Wergedal ◽  
Mark Rehage ◽  
Kiet Tran ◽  
Jacqueline Newton ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transgenic Mice ◽  
Plasma Protein ◽  
Type I ◽  
Osteoblast Proliferation ◽  
Bone Formation Rate ◽  
Igf I ◽  
Proliferation In Vitro

Pregnancy-associated plasma protein (PAPP)-A, a protease for IGF binding protein (IGFBP)-2, -4, and -5, may enhance IGF action by increasing its bioavailability. Here we have determined the role and mechanism of action of PAPP-A in the regulation of osteoblast proliferation in vitro and bone metabolism in vivo. Recombinant PAPP-A (100 ng/ml) significantly increased osteoblast proliferation and free IGF-I concentration. These effects were abolished by noncleavable IGFBP-4, suggesting that PAPP-A promotes osteoblast proliferation by increasing IGF bioavailability. To determine whether PAPP-A exerts an anabolic effect on bone in vivo, we developed transgenic mice that overexpress PAPP-A in osteoblasts using the 2.3-kb rat type I collagen promoter. Consistent with the increase in IGFBP-4 proteolysis, free IGF-I concentration was significantly increased in the conditioned medium of cultured osteoblasts derived from transgenic mice compared with the wild-type littermates. Calvarial bone thickness, bone marrow cavity, and skull bone mineral density were significantly increased in transgenic mice. Bone size-related parameters in femur and tibia such as total bone area and periosteal circumference as determined by peripheral quantitated computed tomography and histological analysis were significantly increased in transgenic mice. Bone formation rate and osteoid surface were increased by more than 2-fold, whereas bone resorbing surface was unaffected. These anabolic effects were sustained with aging. These findings provide strong evidence that PAPP-A acts as a potent anabolic factor in the regulation of bone formation. Thus, enhancing IGF bioavailability by PAPP-A can be a powerful strategy in the treatment of certain metabolic diseases such as osteoporosis.

Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by γ-carboxylation-dependent and -independent mechanisms

2009 ◽  
Vol 297 (6) ◽  
pp. C1358-C1367 ◽  
Author(s):  
Gerald J. Atkins ◽  
Katie J. Welldon ◽  
Asiri R. Wijenayaka ◽  
Lynda F. Bonewald ◽  
David M. Findlay
Keyword(s):  
Bone Formation ◽  
Vitamin K ◽  
Type I Collagen ◽  
Vitamin K2 ◽  
Type I ◽  
Vitamin K1 ◽  
Vitamin K3 ◽  
Positive Effect

The vitamin K family members phylloquinone (vitamin K1) and the menaquinones (vitamin K2) are under study for their roles in bone metabolism and as potential therapeutic agents for skeletal diseases. We have investigated the effects of two naturally occurring homologs, phytonadione (vitamin K1) and menatetrenone (vitamin K2), and those of the synthetic vitamin K, menadione (vitamin K3), on human primary osteoblasts. All homologs promoted in vitro mineralization by these cells. Vitamin K1-induced mineralization was highly sensitive to warfarin, whereas that induced by vitamins K2 and K3 was less sensitive, implying that γ-carboxylation and other mechanisms, possibly genomic actions through activation of the steroid xenobiotic receptor, are involved in the effect. The positive effect on mineralization was associated with decreased matrix synthesis, evidenced by a decrease from control in expression of type I collagen mRNA, implying a maturational effect. Incubation in the presence of vitamin K2 or K3 in a three-dimensional type I collagen gel culture system resulted in increased numbers of cells with elongated cytoplasmic processes resembling osteocytes. This effect was not warfarin sensitive. Addition of calcein to vitamin K-treated cells revealed vitamin K-dependent deposition of mineral associated with cell processes. These effects are consistent with vitamin K promoting the osteoblast-to-osteocyte transition in humans. To test whether vitamin K may also act on mature osteocytes, we tested the effects of vitamin K on MLO-Y4 cells. Vitamin K reduced receptor activator of NF-κB ligand expression relative to osteoprotegerin by MLO-Y4 cells, an effect also seen in human cultures. Together, our findings suggest that vitamin K promotes the osteoblast-to-osteocyte transition, at the same time decreasing the osteoclastogenic potential of these cells. These may be mechanisms by which vitamin K optimizes bone formation and integrity in vivo and may help explain the net positive effect of vitamin K on bone formation.

scholarly journals Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Rosiglitazone Suppresses Components of the Insulin-Like Growth Factor Regulatory System in Vitro and in Vivo

Endocrinology ◽  
2007 ◽  
Vol 148 (2) ◽  
pp. 903-911 ◽  
Author(s):  
B. Lecka-Czernik ◽  
C. Ackert-Bicknell ◽  
M. L. Adamo ◽  
V. Marmolejos ◽  
G. A. Churchill ◽  
...  
Keyword(s):  
Regulatory System ◽  
Peroxisome Proliferator ◽  
Type I ◽  
Peroxisome Proliferator Activated Receptor ◽  
Igf I ◽  
Stromal Cell Line ◽  
Igf Receptor

Rosiglitazone (Rosi) belongs to the class of thiazolidinediones (TZDs) that are ligands for peroxisome proliferator-activated receptor γ (PPARγ). Stimulation of PPARγ suppresses bone formation and enhances marrow adipogenesis. We hypothesized that activation of PPARγ down-regulates components of the IGF regulatory system, leading to impaired osteoblast function. Rosi treatment (1 μm) of a marrow stromal cell line (UAMS-33) transfected with empty vector (U-33/c) or with PPARγ2 (U-33/γ2) were analyzed by microarray. Rosi reduced IGF-I, IGF-II, IGFBP-4, and the type I and II IGF receptor (IGF1R and IGF2R) expression at 72 h in U-33/γ2 compared with U-33/c cells (P < 0.01); these findings were confirmed by RT-PCR. Rosi reduced secreted IGF-I from U-33/γ2 cells by 75% (P < 0.05). Primary marrow stromal cells (MSCs) extracted from adult (8 months) and old (24 months) C57BL/6J (B6) mice were treated with Rosi (1 μm) for 48 h. IGF-I, IGFBP-4, and IGF1R transcripts were reduced in Rosi-treated MSCs compared with vehicle (P < 0.01) and secreted IGF-I was also suppressed (P < 0.05). B6 mice treated with Rosi (20 mg/kg·d) for short duration (i.e. 4 d), and long term (i.e. 7 wk) had reduced serum IGF-I; this was accompanied by markedly suppressed IGF-I transcripts in the liver and peripheral fat of treated animals. To determine whether Rosi affected circulating IGF-I in humans, we measured serum IGF-I, IGFBP-2, and IGFBP-3 at four time points in 50 postmenopausal women randomized to either Rosi (8 mg/d) or placebo. Rosi-treated subjects had significantly lower IGF-I at 8 wk than baseline (−25%, P < 0.05), and at 16 wk their levels were reduced 14% vs. placebo (P = 0.15). We conclude that Rosi suppresses IGF-I expression in bone and liver; these changes could affect skeletal acquisition through endocrine and paracrine pathways.

Experimental Study on the Osteoinduction of Calcium Phosphate Biomaterials In Vivo and the Capability of Supporting Osteoblast Proliferation In Vitro

2005 ◽  
Vol 288-289 ◽  
pp. 281-286 ◽  
Author(s):  
C.Y. Bao ◽  
P. Li ◽  
Yan Fei Tan ◽  
Y. Cao ◽  
Xiao Yan Lin ◽  
...  
Keyword(s):  
Experimental Study ◽  
Surface Modification ◽  
Calcium Phosphate ◽  
Treated Group ◽  
Osteoblast Proliferation ◽  
Thin Slices ◽  
Proliferation In Vitro ◽  
Ceramic Cylinder

The purpose of this study was to evaluate the response of osteoblasts to calcium phosphate with different surface modification, and to evaluate the osteoinductive capabilities of these biomaterials. 60HA/40α-TCP ceramics sintered at 1250oC was applied in this study. A ceramic cylinder with F5mm×8mm and slice with F10mm×1mm were prepared respectively. One third of the ceramics was used to form bone-like apatite (BLA), and the surface of another one third was modified with collagen. Osteoblasts (1×106/ml) were co-cultured with the three kinds of thin slices for 12h, 24h and 48h. SEM observation was applied to evaluate whether the surface modification and BLA formation could affect the attachment and proliferation of osteoblast in vitro. The three kinds of cylinder samples were implanted in dog muscle to evaluate their differences in osteoinduction. Cells grew in multi-layers and attached to the surface and proliferated well in the collagen and HA/TCP group. In the untreated and BLA precipitated groups, cells did not attach to the surface well. Osteoinduction was good in the BLA precipitated group and the amount of bone formed was higher; in the untreated group and collagen-treated group, no bone formation was observed in the tested period. This result indicated that the scaffold used in cell-materials composites in vitro and that in osteoinductive material based tissue engineering in vivo was not same.

Parathyroid hormone potentiates the effect of insulin-like growth factor-I on bone formation

1989 ◽  
Vol 121 (3) ◽  
pp. 435-442 ◽  
Author(s):  
E. Martin Spencer ◽  
Erwin C. C. Si ◽  
Chung C. Liu ◽  
Guy A. Howard
Keyword(s):  
Parathyroid Hormone ◽  
Growth Factor ◽  
Bone Formation ◽  
Trabecular Bone ◽  
Thymidine Incorporation ◽  
Bone Apposition ◽  
Factor I ◽  
Igf I

Abstract. Insulin-like growth factor-I and parathyroid hormone are both known regulators of bone formation. In this study, human recombinant IGF-I and bovine PTH (1–34) and their combination were studied for their effects in vitro on the proliferation of embryonic chick osteoblast-like cells (osteoblasts) and in vivo on bone formation in normal rats. Osteoblasts from 17-day-old chick embryos were cultured in serum-free BGJb medium containing 0.1% bovine albumin. After 2 days, IGF-I and/or PTH were added. Twenty-four hours later [3H]thymidine incorporation into trichloroacetic acid precipitable material was quantified as an index of cell proliferation. This has previously been shown to reflect actual cell division. IGF-I at doses ranging from 0.85 to 13.6 nmol/l caused a dose-dependent increase in [3H]thymidine incorporation into osteoblasts. PTH alone (10 to 1000 pmol/l) had no significant effect. However, when combined with IGF-I, PTH potentiated the mitogenic effect of IGF-I and achieved statistical significance at 30 and 100 pmol/l (p <0.05). This potentiation was also studied in vivo. The right hindlimbs of rats weighing 150 g were infused intra-arterially by an osmotic minipump with graded doses of IGF-I (0.1 to 0.4 nmol/day) and/or PTH (0.27 nmol/day) for 7 days. The rate of trabecular bone apposition (formation) was measured by double tetracycline labelling and compared with the contralateral uninfused limb which acted as the control. Histomorphometric data revaled that neither IGF-I nor PTH alone had a significant effect on trabecular bone apposition rate compared with control limbs. The co-infusion of IGF-I (0.4 nmol/day) and PTH (0.27 nmol/day) resulted in a marked increase in trabecular bone apposition rate. The results of 2 studies were significant at p < 0.01. These data suggest that PTH potentiates the effect of IGF-I on bone formation both in vivo and in vitro.

scholarly journals CD13 is a Critical Regulator of Cell-cell Fusion in Osteoclastogenesis

2020 ◽  
Author(s):  
Mallika Ghosh ◽  
Ivo Kalajzic ◽  
Hector Leonardo Aguila ◽  
Linda H Shapiro
Keyword(s):  
Bone Marrow ◽  
Bone Formation ◽  
Progenitor Cells ◽  
Cell Fusion ◽  
Formation Rate ◽  
Giant Cells ◽  
Bone Formation Rate ◽  
Cell Cell

AbstractIn vertebrates, bone formation is dynamically controlled by the activity of two specialized cell types: the bone-generating osteoblasts and bone-degrading osteoclasts. Osteoblasts produce the soluble receptor activator of NFκB ligand (RANKL) that binds to its receptor RANK on the surface of osteoclast precursor cells to promote osteoclastogenesis, a process that involves cell-cell fusion and assembly of molecular machinery to ultimately degrade the bone. CD13 is a transmembrane aminopeptidase that is highly expressed in cells of myeloid lineage has been shown to regulate dynamin-dependent receptor endocytosis and recycling and is a necessary component of actin cytoskeletal organization. In the present study, we show that CD13-deficient mice display a normal distribution of osteoclast progenitor populations in the bone marrow, but present a low bone density phenotype. Further, the endosteal bone formation rate is similar between genotypes, indicating a defect in osteoclast-specific function in vivo. Loss of CD13 led to exaggerated in vitro osteoclastogenesis as indicated by significantly enhanced fusion of bone marrow-derived multinucleated osteoclasts in the presence of M-CSF and RANKL, resulting in abnormally large cells with remarkably high numbers of nuclei with a concomitant increase in bone resorption activity. Similarly, we also observed increased formation of multinucleated giant cells (MGC) in CD13KO bone marrow progenitor cells stimulated with IL-4 and IL-13, suggesting that CD13 may regulate cell-cell fusion events via a common pathway, independent of RANKL signaling. Mechanistically, while expression levels of the fusion-regulatory proteins dynamin and DC-STAMP are normally downregulated as fusion progresses in fusion-competent mononucleated progenitor cells, in the absence of CD13 they are uniformly sustained at high levels, even in mature multi-nucleated osteoclasts. Taken together, we conclude that CD13 may regulate cell-cell fusion by controlling expression and localization of key fusion proteins that are critical for both osteoclast and MGC fusion.

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