scholarly journals Osteoblastic Responses to TGF-β during Bone Remodeling

1998 ◽  
Vol 9 (7) ◽  
pp. 1903-1918 ◽  
Author(s):  
Adrian Erlebacher ◽  
Ellen H. Filvaroff ◽  
Jian-Qin Ye ◽  
Rik Derynck
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Transgenic Mice ◽  
Bone Remodeling ◽  
Osteoblast Differentiation ◽  
Bone Matrix ◽  
Physiological Role ◽  
Dominant Negative ◽  
Central Component ◽  
Physiological Regulator

Bone remodeling depends on the spatial and temporal coupling of bone formation by osteoblasts and bone resorption by osteoclasts; however, the molecular basis of these inductive interactions is unknown. We have previously shown that osteoblastic overexpression of TGF-β2 in transgenic mice deregulates bone remodeling and leads to an age-dependent loss of bone mass that resembles high-turnover osteoporosis in humans. This phenotype implicates TGF-β2 as a physiological regulator of bone remodeling and raises the question of how this single secreted factor regulates the functions of osteoblasts and osteoclasts and coordinates their opposing activities in vivo. To gain insight into the physiological role of TGF-β in bone remodeling, we have now characterized the responses of osteoblasts to TGF-β in these transgenic mice. We took advantage of the ability of alendronate to specifically inhibit bone resorption, the lack of osteoclast activity in c-fos −/− mice, and a new transgenic mouse line that expresses a dominant-negative form of the type II TGF-β receptor in osteoblasts. Our results show that TGF-β directly increases the steady-state rate of osteoblastic differentiation from osteoprogenitor cell to terminally differentiated osteocyte and thereby increases the final density of osteocytes embedded within bone matrix. Mice overexpressing TGF-β2 also have increased rates of bone matrix formation; however, this activity does not result from a direct effect of TGF-β on osteoblasts, but is more likely a homeostatic response to the increase in bone resorption caused by TGF-β. Lastly, we find that osteoclastic activity contributes to the TGF-β–induced increase in osteoblast differentiation at sites of bone resorption. These results suggest that TGF-β is a physiological regulator of osteoblast differentiation and acts as a central component of the coupling of bone formation to resorption during bone remodeling.

scholarly journals Decreased C-Src Expression Enhances Osteoblast Differentiation and Bone Formation

2000 ◽  
Vol 151 (2) ◽  
pp. 311-320 ◽  
Author(s):  
Marilena Marzia ◽  
Natalie A. Sims ◽  
Susanne Voit ◽  
Silvia Migliaccio ◽  
Anna Taranta ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Matrix Protein ◽  
Bone Matrix ◽  
Osteogenic Cells ◽  
Alp Activity ◽  
Pthrp Receptor ◽  
Bone Matrix Protein

c-src deletion in mice leads to osteopetrosis as a result of reduced bone resorption due to an alteration of the osteoclast. We report that deletion/reduction of Src expression enhances osteoblast differentiation and bone formation, contributing to the increase in bone mass. Bone histomorphometry showed that bone formation was increased in Src null compared with wild-type mice. In vitro, alkaline phosphatase (ALP) activity and nodule mineralization were increased in primary calvarial cells and in SV40-immortalized osteoblasts from Src−/− relative to Src+/+ mice. Src-antisense oligodeoxynucleotides (AS-src) reduced Src levels by ∼60% and caused a similar increase in ALP activity and nodule mineralization in primary osteoblasts in vitro. Reduction in cell proliferation was observed in primary and immortalized Src−/− osteoblasts and in normal osteoblasts incubated with the AS-src. Semiquantitative reverse transcriptase-PCR revealed upregulation of ALP, Osf2/Cbfa1 transcription factor, PTH/PTHrP receptor, osteocalcin, and pro-alpha 2(I) collagen in Src-deficient osteoblasts. The expression of the bone matrix protein osteopontin remained unchanged. Based on these results, we conclude that the reduction of Src expression not only inhibits bone resorption, but also stimulates osteoblast differentiation and bone formation, suggesting that the osteogenic cells may contribute to the development of the osteopetrotic phenotype in Src-deficient mice.

scholarly journals Bone morphogenetic protein receptor signaling is necessary for normal murine postnatal bone formation

2002 ◽  
Vol 157 (6) ◽  
pp. 1049-1060 ◽  
Author(s):  
Ming Zhao ◽  
Stephen E. Harris ◽  
Diane Horn ◽  
Zhaopo Geng ◽  
Riko Nishimura ◽  
...  
Keyword(s):  
Bone Formation ◽  
Transgenic Mice ◽  
Bone Matrix ◽  
Dominant Negative ◽  
Type I ◽  
Receptor Signaling ◽  
Mineral Density ◽  
Bmp Receptor

Functions of bone morphogenetic proteins (BMPs) are initiated by signaling through specific type I and type II serine/threonine kinase receptors. In previous studies, we have demonstrated that the type IB BMP receptor (BMPR-IB) plays an essential and specific role in osteoblast commitment and differentiation. To determine the role of BMP receptor signaling in bone formation in vivo, we generated transgenic mice, which express a truncated dominant-negative BMPR-IB targeted to osteoblasts using the type I collagen promoter. The mice are viable and fertile. Tissue-specific expression of the truncated BMPR-IB was demonstrated. Characterization of the phenotype of these transgenic mice showed impairment of postnatal bone formation in 1-mo-old homozygous transgenic mice. Bone mineral density, bone volume, and bone formation rates were severely reduced, but osteoblast and osteoclast numbers were not significantly changed in the transgenic mice. To determine whether osteoblast differentiation is impaired, we used primary osteoblasts isolated from the transgenic mice and showed that BMP signaling is blocked and BMP2-induced mineralized bone matrix formation was inhibited. These studies show the effects of alterations in BMP receptor function targeted to the osteoblast lineage and demonstrate a necessary role of BMP receptor signaling in postnatal bone growth and bone formation in vivo.

scholarly journals Cigarette smoke-associated inflammation impairs bone remodeling through NFκB activation

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yi Lu ◽  
Yuanpu Peter Di ◽  
Ming Chang ◽  
Xin Huang ◽  
Qiuyan Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Cigarette Smoke ◽  
Osteoblast Differentiation ◽  
Bone Structure ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Bone Homeostasis

Abstract Background Cigarette smoking constitutes a major lifestyle risk factor for osteoporosis and hip fracture. It is reported to impair the outcome of many clinical procedures, such as wound infection treatment and fracture healing. Importantly, although several studies have already demonstrated the negative correlation between cigarette consume and impaired bone homeostasis, there is still a poor understanding of how does smoking affect bone health, due to the lack of an adequately designed animal model. Our goal was to determine that cigarette smoke exposure impairs the dynamic bone remodeling process through induction of bone resorption and inhibition of bone formation. Methods We developed cigarette smoke exposure protocols exposing mice to environmental smoking for 10 days or 3 months to determine acute and chronic smoke exposure effects. We used these models, to demonstrate the effect of smoking exposure on the cellular and molecular changes of bone remodeling and correlate these early alterations with subsequent bone structure changes measured by microCT and pQCT. We examined the bone phenotype alterations in vivo and ex vivo in the acute and chronic smoke exposure mice by measuring bone mineral density and bone histomorphometry. Further, we measured osteoclast and osteoblast differentiation gene expression levels in each group. The function changes of osteoclast or osteoblast were evaluated. Results Smoke exposure caused a significant imbalance between bone resorption and bone formation. A 10-day exposure to cigarette smoke sufficiently and effectively induced osteoclast activity, leading to the inhibition of osteoblast differentiation, although it did not immediately alter bone structure as demonstrated in mice exposed to smoke for 3 months. Cigarette smoke exposure also induced DNA-binding activity of nuclear factor kappaB (NFκB) in osteoclasts, which subsequently gave rise to changes in bone remodeling-related gene expression. Conclusions Our findings suggest that smoke exposure induces RANKL activation-mediated by NFκB, which could be a “smoke sensor” for bone remodeling.

scholarly journals The Development of Molecular Biology of Osteoporosis

2021 ◽  
Vol 22 (15) ◽  
pp. 8182
Author(s):  
Yongguang Gao ◽  
Suryaji Patil ◽  
Jingxian Jia
Keyword(s):  
Bone Resorption ◽  
Molecular Biology ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Cell Activity ◽  
Bone Cell ◽  
Bone Disorders ◽  
Molecular Aspects

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.

scholarly journals The Effect of the Combination of Vitamin K2 and Genistein, Coumestrol and Daidzein on the Osteoblast Differentiation and Bone Matrix Formation

2016 ◽  
Vol 10 (2) ◽  
pp. 12-19
Author(s):  
Sahar S. Karieb ◽  
Mohammed M. Jawad ◽  
Hanady S. Al-Shmgani ◽  
Zahraa H.M. Kadri
Keyword(s):  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Nuclear Factor Kappa B ◽  
Type I Collagen ◽  
Bone Mineralization ◽  
Bone Matrix ◽  
Vitamin K2 ◽  
Type I ◽  
Nuclear Factor ◽  
Effective Factor

Multiple studies have been reported the stimulatory effect of the combinations of nutrients factors on bone formation. One such factor is vitamin K2 which can be associated with bone protective activities. The effect of vitamin K2 alone and in combination with genistein, coumestrol and daidzein on osteoblast differentiation and mineralization were tested. Significantly, vitamin K2 increased bone mineralization in combination with genistein (10-5M), coumestrol (10-7M) and daidzein (10-5M). However, there is no additive effect of this vitamin on alkaline phosphatase (ALP) levels in osteoblasts. By contrast, vitamin K2 enhanced the stimulatory effect of type I collagen and osteocalcin expression. Vitamin K2 alone increased RUNX and OSX expression while there is no synergistic effect with tested compound; this vitamin also did not modulate nuclear factor kappa B ligand (RANKL)/ osteoprotegerin (OPG) ratio expression. These results suggested that vitamin K2 can be more effective factor in the presence of phytoestrogens on the improvement of bone formation after menopause.

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

1989 ◽  
Vol 7 (12) ◽  
pp. 1909-1914 ◽  
Author(s):  
R Bataille ◽  
D Chappard ◽  
C Marcelli ◽  
P Dessauw ◽  
J Sany ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Cell Mass ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Bone Lesions ◽  
Mass Reduction

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

scholarly journals High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

2002 ◽  
Vol 22 (17) ◽  
pp. 6222-6233 ◽  
Author(s):  
Valérie Geoffroy ◽  
Michaela Kneissel ◽  
Brigitte Fournier ◽  
Alan Boyde ◽  
Patrick Matthias
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Formation ◽  
Transgenic Mice ◽  
Wild Type ◽  
Osteoblastic Lineage ◽  
High Bone ◽  
Transgenic Cells ◽  
Primary Osteoblasts ◽  
In Cells

ABSTRACT The runt family transcription factor core-binding factor α1 (Cbfa1) is essential for bone formation during development. Surprisingly, transgenic mice overexpressing Cbfa1 under the control of the 2.3-kb collagen type I promoter developed severe osteopenia that increased progressively with age and presented multiple fractures. Analysis of skeletally mature transgenic mice showed that osteoblast maturation was affected and that specifically in cortical bone, bone resorption as well as bone formation was increased, inducing high bone turnover rates and a decreased degree of mineralization. To understand the origin of the increased bone resorption, we developed bone marrow stromal cell cultures and reciprocal coculture of primary osteoblasts and spleen cells from wild-type or transgenic mice. We showed that transgenic cells of the osteoblastic lineage induced an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells, suggesting that primary osteoblasts as well as bone marrow stromal cells from transgenic mice have stronger osteoclastogenic properties than cells derived from wild-type animals. We investigated the candidate genes whose altered expression could trigger this increase in bone resorption, and we found that the expression of receptor activator of NF-κB ligand (RANKL) and collagenase 3, two factors involved in bone formation-resorption coupling, was markedly increased in transgenic cells. Our data thus suggest that overexpression of Cbfa1 in cells of the osteoblastic lineage does not necessarily induce a substantial increase in bone formation in the adult skeleton but has a positive effect on osteoclast differentiation in vitro and can also dramatically enhance bone resorption in vivo, possibly through increased RANKL expression.

scholarly journals Enhancement of Osteoclastic Bone Resorption and Suppression of Osteoblastic Bone Formation in Response to Reduced Mechanical Stress Do Not Occur in the Absence of Osteopontin

2001 ◽  
Vol 193 (3) ◽  
pp. 399-404 ◽  
Author(s):  
Muneaki Ishijima ◽  
Susan R. Rittling ◽  
Teruhito Yamashita ◽  
Kunikazu Tsuji ◽  
Hisashi Kurosawa ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Mechanical Stress ◽  
Bone Matrix ◽  
Osteoclastic Bone Resorption ◽  
Tail Suspension ◽  
Wild Type ◽  
Osteoblastic Bone Formation

Reduced mechanical stress to bone in bedridden patients and astronauts leads to bone loss and increase in fracture risk which is one of the major medical and health issues in modern aging society and space medicine. However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date. Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known. To investigate the possible requirement for OPN in the transduction of mechanical signaling in bone metabolism in vivo, we examined the effect of unloading on the bones of OPN−/− mice using a tail suspension model. In contrast to the tail suspension–induced bone loss in wild-type mice, OPN−/− mice did not lose bone. Elevation of urinary deoxypyridinoline levels due to unloading was observed in wild-type but not in OPN−/− mice. Analysis of the mechanisms of OPN deficiency–dependent reduction in bone on the cellular basis resulted in two unexpected findings. First, osteoclasts, which were increased by unloading in wild-type mice, were not increased by tail suspension in OPN−/− mice. Second, measures of osteoblastic bone formation, which were decreased in wild-type mice by unloading, were not altered in OPN−/− mice. These observations indicate that the presence of OPN is a prerequisite for the activation of osteoclastic bone resorption and for the reduction in osteoblastic bone formation in unloaded mice. Thus, OPN is a molecule required for the bone loss induced by mechanical stress that regulates the functions of osteoblasts and osteoclasts.

Bortezomib Reduces Serum Dickkopf-1 and RANKL Concentrations and Normalizes Indices of Bone Remodeling in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 506-506
Author(s):  
Evangelos Terpos ◽  
Deborah Heath ◽  
Amin Rahemtulla ◽  
Kostas Zervas ◽  
Andrew Chantry ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Serum Levels ◽  
Response To Therapy ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Lytic Lesions ◽  
Tracp 5B ◽  
Dickkopf 1

Abstract Bortezomib is a proteasome inhibitor, which is currently indicated for the treatment of relapsed/refractory myeloma (MM). Although the anti-myeloma effect of bortezomib has been clearly demonstrated, its effect on bone metabolism is still unclear. There are recent reports that bortezomib increases serum alkaline phosphatase (ALP) activity, which is consistent with enhanced osteoblast function. The aim of this study was to evaluate the effect of bortezomib on bone turnover in 34 patients with relapsed MM. Bortezomib was given alone at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle for 4 cycles. Responders could continue for 4 more cycles, while non-responders could continue therapy with the addition of dexamethasone. The following serum indices were measured on day 1 of cycle 1, and then on day 21 of cycles 4 and 8: osteoblast inhibitor dickkopf-1 (DKK-1); osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG); bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC). We also studied 33 healthy controls of similar gender and age. The objective response rate after 4 cycles of therapy was 66%: CR 8% and PR 58%. Sixteen responders and 3 non-responders continued on therapy for 4 more cycles. Myeloma patients at baseline had increased values of DKK-1 (p=0.007), sRANKL, sRANKL/OPG ratio, and both markers of bone resorption (p<0.0001) when compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.001). There was a strong correlation between bone lytic disease and serum CTX (r=0.59, p<0.01), and sRANKL (r=0.4, p=0.03). Patients with severe bone disease (>9 lytic lesions, n=7) had elevated values of DKK-1 compared with all others (mean±SD: 223.4±264.4 ng/mL vs. 84±62.4 ng/mL; p=0.01). Moreover, serum levels of DKK-1 correlated with CTX levels (r=0.39, p=0.04), and weakly with bALP concentrations (r=−0.32, p=0.09). The administration of bortezomib produced a significant reduction of DKK-1 (p=0.035), sRANKL (p=0.01), CTX and TRACP-5b (p<0.001) after 4 cycles, which was still seen after 8 cycles of treatment (p<0.01). Bortezomib also produced a dramatic increase in both markers of bone formation, bALP and OC, after 4 and 8 cycles of therapy (p<0.01). Responders tended to have lower initial levels of DKK-1 compared with non-responders. Patients who achieved a CR or vgPR after 4 cycles of bortezomib had greater elevation of bALP than all others: mean±SD of increase: 306.3%±556.9% vs. 45.8%±56.5%; p=0.02. It is of interest that 3/4 non responders also had an increase in bALP (mean: 39.6%) after 4 cycles of bortezomib. There was no other correlation between response to therapy and alteration of bone markers. No healing of the lytic lesions was observed even in CR patients. This study suggests that bortezomib reduces serum levels of DKK-1 and RANKL, irrespective of response to therapy, in patients with relapsed myeloma and thus leads to normalization of abnormal bone remodeling through the increase of bone formation and reduction of bone resorption.

The effect of tai chi chuan on bone remodeling and cytokines among breast cancer survivors: A feasibility trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9610-9610
Author(s):  
L. J. Peppone ◽  
K. Mustian ◽  
R. N. Rosier ◽  
K. M. Piazza ◽  
D. G. Hicks ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Bone Health ◽  
Tai Chi ◽  
Cell Function ◽  
Bone Cell ◽  
Post Intervention ◽  
Tai Chi Chuan

9610 Background: Weight-bearing exercise may slow the rate of bone loss associated with breast cancer treatment. The purpose of this study is to determine the effect of tai chi chuan (TCC) on bone health, as measured by the changes in the levels of bone resorption and bone formation. This study also aimed to investigate whether changes in bone health were correlated with growth and inflammation markers that serve as regulators of bone cell function. Methods: Female patients (N=16) who completed treatment for breast cancer within the past 30 months were randomly assigned to either the TCC group or the psycho-educational support group without exercise (ST) for 60 minutes, three times a week for a period of 12 weeks. Serum levels of bone resorption (N-telopeptides of type I collagen; NTx) and bone formation (bone specific alkaline phosphatase; BAP) were determined by ELISA at baseline and post-intervention. Using validated methods, a bone remodeling index (BRI) was calculated from levels of NTx and BAP. In addition, pre- and post-intervention levels of insulin-like growth factor binding protein 1 (IGFBP-1) and interleukin-2 (IL-2), markers associated with excessive bone resorption, were measured. Lastly, levels of interleukin-6 (IL-6), believed to enhance bone formation, were measured at both pre- and post-intervention. Results: ANCOVA analyses demonstrated that survivors in the TCC group experienced a greater increase in bone remodeling than those in the ST group (Δ BRITCC=1.6 vs Δ BRIST=0.2; p=0.04). All correlations were determined by Pearson's correlation coefficients. IGFBP-1 was negatively correlated with increasing bone remodeling levels (r=-0.43, p=0.14). IL-2 was also negatively correlated with increasing bone remodeling levels (r=-0.35, p=0.24). IL-6 was positively correlated with increasing bone remodeling levels (r=0.69, p=0.01). Conclusions: This pilot study suggests that TCC has positive effects on bone remodeling through changes in growth and inflammation factors that regulate bone cell function. A larger, more definitive trial examining the influence of TCC on bone remodeling is warranted. Funding: Sally Schindel Cone and R25 CA102618 No significant financial relationships to disclose.

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