scholarly journals Thymidine Phosphorylase Exerts Complex Effects on Bone Resorption and Formation in Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1135-1135
Author(s):  
Huan Liu ◽  
Zhiqiang Liu ◽  
Juan Du ◽  
Jin He ◽  
Pei Lin ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Osteoblast Differentiation ◽  
Thymidine Phosphorylase ◽  
Osteoclast Differentiation ◽  
Akt Signaling ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Lytic Lesions

Abstract Thymidine phosphorylase (TP), an enzyme that can reversibly catalyze the conversion of thymidine to thymine and 2-deoxy-D-ribose (2DDR), has been shown to participate in tumor angiogenesis and proliferation. Yet little is known regarding its function in bone. The goal of this study is to elucidate the role and mechanism of myeloma-expressed TP in the activation of osteoclast-mediated bone resorption and the suppression of osteoblast-mediated bone formation. We hypothesized that myeloma-expressed TP plays an important role in the pathogenesis of myeloma bone disease. We observed that TP is highly expressed in myeloma cells but not in normal plasma cells. To examine the role of myeloma-expressed TP in lytic bone lesions, we categorized all tested patient-derived myeloma cells and human myeloma cell lines into two groups: TP-high and TP-low expressing cells. These myeloma cells, as well as human myeloma cells with overexpressed or knocked downed levels of TP, were injected into the implanted human bone chips of SCID-hu mice or the femurs of SCID mice. Analysis of radiography and histomorphometry were used for assessing lytic lesions. Our results showed that injection of TP-high expressing myeloma cells into mice caused more lytic lesions than injection of TP-low cells. To examine its role in osteoclast and osteoblast differentiation, the progenitors were co-cultured with the myeloma cells, and analyzed with staining of TRAP and Alizarin red S. We observed that co-culture with TP-high expressing myeloma cells induced more osteoclast differentiation and less osteoblast formation than those co-cultured with TP-low cells. Mechanistic studies further showed that TP-high expressing myeloma cells secreted more 2DDR than TP-low cells. The secreted 2DDR bound to the integrin aVb3 in osteoclast progenitors, activated the PI3K/Akt signaling, and enhanced DNMT3A expression and methylation of IRF8, leading to increased NFATc1 expression and osteoclast differentiation. The secreted 2DDR could also bind to the integrins aVb3 and a5b1 in osteoblast progenitors, activated the PI3K/Akt signaling, and enhanced DNMT3A expression and methylation of RUNX2 and osterix, leading to decreased osteoblast differentiation. We further examined the patient bone marrow samples, and demonstrated a positive correlation between TP expression in myeloma cells and osteolytic bone lesions in myeloma patients. Thus, our study not only elucidates a novel mechanism of myeloma-induced increased osteoclast-mediated bone resorption and suppressed osteoblast-mediated bone formation, but also implicates a potential therapeutic approach for myeloma bone disease. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mechanism of Action of Bortezomib and the New Proteasome Inhibitors on Myeloma Cells and the Bone Microenvironment: Impact on Myeloma-Induced Alterations of Bone Remodeling

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Fabrizio Accardi ◽  
Denise Toscani ◽  
Marina Bolzoni ◽  
Benedetta Dalla Palma ◽  
Franco Aversa ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Osteoblast Differentiation ◽  
Clinical Evidence ◽  
Osteoclast Differentiation ◽  
Proteasome Inhibitors ◽  
High Capacity ◽  
Bone Lesions ◽  
Myeloma Bone Disease ◽  
Receptor Activator ◽  
Turnover Markers

Multiple myeloma (MM) is characterized by a high capacity to induce alterations in the bone remodeling process. The increase in osteoclastogenesis and the suppression of osteoblast formation are both involved in the pathophysiology of the bone lesions in MM. The proteasome inhibitor (PI) bortezomib is the first drug designed and approved for the treatment of MM patients by targeting the proteasome. However, recently novel PIs have been developed to overcome bortezomib resistance. Interestingly, several preclinical data indicate that the proteasome complex is involved in both osteoclast and osteoblast formation. It is also evident that bortezomib either inhibits osteoclast differentiation induced by the receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) or stimulates the osteoblast differentiation. Similarly, the new PIs including carfilzomib and ixazomib can inhibit bone resorption and stimulate the osteoblast differentiation. In a clinical setting, PIs restore the abnormal bone remodeling by normalizing the levels of bone turnover markers. In addition, a bone anabolic effect was described in responding MM patients treated with PIs, as demonstrated by the increase in the osteoblast number. This review summarizes the preclinical and clinical evidence on the effects of bortezomib and other new PIs on myeloma bone disease.

Anti-Sclerostin Treatment Prevents Multiple Myeloma Induced Bone Loss and Reduces Tumor Burden

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 119-119 ◽  
Author(s):  
Michaela R. Reagan ◽  
Michelle McDonald ◽  
Rachael Terry ◽  
Jessica Pettitt ◽  
Lawrence Le ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Loss ◽  
Bone Formation ◽  
Tumor Growth ◽  
Bone Disease ◽  
Bone Volume ◽  
Antibody Treatment ◽  
Myeloma Cells ◽  
Myeloma Bone Disease

Abstract Multiple myeloma (MM) is a malignancy of plasma cells and is characterized by unrestricted tumor cell growth in bone marrow (BM). MM causes destructive osteolytic lesions causing bone fracture, bone pain, hypercalcaemia, and nerve-compression, resulting from increased bone resorption and suppressed bone formation. Despite the introduction of agents to inhibit bone resorption, such as bisphosphonates, which prevent further bone loss, approaches to preventing osteoblast suppression and repair bone lesions are limited and there are no agents available clinically. The wnt/β-catenin pathway plays a critical role in the regulation of bone formation. Production of the soluble wnt antagonist dickkopf1 (Dkk1) by MM cells has been implicated in MM inhibition of bone formation. As such, Anti-Dkk1 treatment prevents bone disease in pre-clinical models of MM and is in early clinical development. However, Dkk1 is not expressed by all myeloma cells; hence only a proportion of patients may respond to anti-Dkk1 therapy. Sclerostin (Scl) is a soluble wnt antagonist whose expression, unlike Dkk1, is restricted to osteocytes; therefore Scl targeted agents may have less off target effects. Anti-Sclerostin (Anti-Scl) treatment increased bone formation and bone volume in experimental models of osteoporosis, and increased bone mineral density in phase II osteoporosis clinical trials. However, Anti-Scl treatment effects on myeloma bone disease are unknown. Further, cells of the BM such as osteoblasts have been implicated in the regulation of MM cell survival and growth. Thus, in the present study we explored the potential for Anti-Scl therapy to prevent MM induced bone loss and inhibit MM growth in both murine and human xenograft MM models. Female C57BLKalwRij mice (n=8) were injected i.v, with 5TGM1/eGFP murine MM cells (1×106) and female SCID/beige mice (n=10) were injected i.v. with MM1S/Luc/eGFP human MM cells (4 × 106). 24 hours later, naïve mice (without tumor cells) or mice bearing MM cells were treated with anti-sclerostin antibody (Anti-Scl) (100mg/kg i.v) or control antibody. Mice were sacrificed at day 21 (MM1S) or day 28 (5TGM1) and the effect of Anti-Scl on bone structure in the femora and vertebrae were determined by microCT analysis. The effect of Anti-Scl on MM burden was determined by bioluminescent imaging (BLI) performed twice weekly from week 1 using a Xenogen IVIS system, whereas MM burden in 5TGM1/eGFP bearing mice was examined by FACS analysis. Anti-Scl treatment in naïve C57BLKalwRij mice increased trabecular bone volume fraction (BV/TV, 39%, p<0.01, Fig. 1B) in the femur, which was mediated by increases in trabecular thickness (Tb.Th, 42%, p<0.01). Treatment also increased cortical bone volume (22%, p<0.01) in the femur and increased trabecular BV/TV in the vertebra (32%, p<0.01). This demonstrated the potent bone anabolic effect of Anti-Scl independent of myeloma cells. Injection of 5TGM1 cells resulted in a decrease in femoral trabecular BV/TV (30%, p<0.01) through a 30% reduction in trabecular number (TbN) (p<0.01), but no effect on Tb.Th (Figs. 1A and B), whilst also reducing cortical bone volume (BV) by 6% (p<0.05). Vertebrae were also impacted by 5TGM1 tumor growth with a 29% reduction in Tb BV/TV through a 23% reduction in Tb.Th (p<0.01) and also a 15% reduction in cortical BV (p<0.01). Treatment of 5TGM1-bearing mice with Anti-Scl increased trabecular BV/TV (46%, p<0.01) and Tb.Th (30%, p<0.01) to values equivalent to femora of naïve, non-tumor bearing, control mice. Treatment with Anti-Scl also increased cortical BV by 16% (p<0.01), vertebral Tb BV/TV by 29% and cortical BV by 36% in 5TGM1 burdened mice (p<0.01). Treatment of 5TGM1-bearing mice with Anti-Scl had no effect on the proportion 5TGM1/eGFP cells in the BM or spleen. However Anti-Scl treatment significantly suppressed tumor progression in the MM1S model at 3, 3.5 and 4 weeks post cell injection, as determined by BLI imaging (p=0.02, wk 3; p=0.0019, wk 3.5, and p=0.0068, wk 4, 2-tailed t-tests, Fig. 1C). These data demonstrate that Anti-Scl antibody treatment can prevent development of myeloma bone disease. Furthermore, Anti-Scl treatment also suppressed tumor growth, supporting the possibility that targeting the BM microenvironment with this agent may slow disease progression. Our findings highlight the potential clinical application of Anti-Scl antibody treatment in patients with MM and other bone destructive cancers. Disclosures Kneissel: Novartis Institutes for Biomedical Research, Novartis Pharma AG: Employment. Kramer:Novartis Pharma AG: Employment. Brooks:Spouse works for Boston Biomedical Inc: Employment.

scholarly journals Lumican Inhibits Osteoclastogenesis and Bone Resorption by Suppressing Akt Activity

2021 ◽  
Vol 22 (9) ◽  
pp. 4717
Author(s):  
Jin-Young Lee ◽  
Da-Ae Kim ◽  
Eun-Young Kim ◽  
Eun-Ju Chang ◽  
So-Jeong Park ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Map Kinases ◽  
Osteoclast Differentiation ◽  
Dependent Manner ◽  
Dual Action ◽  
Dose Dependent ◽  
Resorptive Activity

Lumican, a ubiquitously expressed small leucine-rich proteoglycan, has been utilized in diverse biological functions. Recent experiments demonstrated that lumican stimulates preosteoblast viability and differentiation, leading to bone formation. To further understand the role of lumican in bone metabolism, we investigated its effects on osteoclast biology. Lumican inhibited both osteoclast differentiation and in vitro bone resorption in a dose-dependent manner. Consistent with this, lumican markedly decreased the expression of osteoclastogenesis markers. Moreover, the migration and fusion of preosteoclasts and the resorptive activity per osteoclast were significantly reduced in the presence of lumican, indicating that this protein affects most stages of osteoclastogenesis. Among RANKL-dependent pathways, lumican inhibited Akt but not MAP kinases such as JNK, p38, and ERK. Importantly, co-treatment with an Akt activator almost completely reversed the effect of lumican on osteoclast differentiation. Taken together, our findings revealed that lumican inhibits osteoclastogenesis by suppressing Akt activity. Thus, lumican plays an osteoprotective role by simultaneously increasing bone formation and decreasing bone resorption, suggesting that it represents a dual-action therapeutic target for osteoporosis.

scholarly journals Network Pharmacology-Based Strategy for the Investigation of the Anti-Osteoporosis Effects and Underlying Mechanism of Zhuangguguanjie Formulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Wang Gong ◽  
Xingren Chen ◽  
Tianshu Shi ◽  
Xiaoyan Shao ◽  
Xueying An ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Signaling Pathway ◽  
Osteoclast Differentiation ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Network Pharmacology ◽  
Biological Processes

As the society is aging, the increasing prevalence of osteoporosis has generated huge social and economic impact, while the drug therapy for osteoporosis is limited due to multiple targets involved in this disease. Zhuangguguanjie formulation (ZG) is extensively used in the clinical treatment of bone and joint diseases, but the underlying mechanism has not been fully described. This study aimed to examine the therapeutic effect and potential mechanism of ZG on postmenopausal osteoporosis. The ovariectomized (OVX) mice were treated with normal saline or ZG for 4 weeks after ovariectomy following a series of analyses. The bone mass density (BMD) and trabecular parameters were examined by micro-CT. Bone remodeling was evaluated by the bone histomorphometry analysis and ELISA assay of bone turnover biomarkers in serum. The possible drug–disease common targets were analyzed by network pharmacology. To predict the potential biological processes and related pathways, GO/KEGG enrichment analysis was performed. The effects of ZG on the differentiation phenotype of osteoclasts and osteoblasts and the predicted pathway were verified in vitro. The results showed that ZG significantly improved the bone mass and micro-trabecular architecture in OVX mice compared with untreated OVX mice. ZG could promote bone formation and inhibit bone resorption to ameliorate ovariectomy-induced osteoporosis as evidenced by increased number of osteoblast (N.Ob/Tb.Pm) and decreased number of osteoclast (N.Oc/Tb.Pm) in treated group compared with untreated OVX mice. After identifying potential drug–disease common targets by network pharmacology, GO enrichment analysis predicted that ZG might affect various biological processes including osteoblastic differentiation and osteoclast differentiation. The KEGG enrichment analysis suggested that PI3K/Akt and mTOR signaling pathways could be the possible pathways. Furthermore, the experiments in vitro validated our findings. ZG significantly down-regulated the expression of osteoclast differentiation markers, reduced osteoclastic resorption, and inhibited the phosphorylation of PI3K/Akt, while ZG obviously up-regulated the expression of osteogenic biomarkers, promoted the formation of calcium nodules, and hampered the phosphorylation of 70S6K1/mTOR, which can be reversed by the corresponding pathway activator. Thus, our study suggested that ZG could inhibit the PI3K/Akt signaling pathway to reduce osteoclastic bone resorption as well as hamper the mTORC1/S6K1 signaling pathway to promote osteoblastic bone formation.

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 Role for macrophage inflammatory protein (MIP)-1α and MIP-1β in the development of osteolytic lesions in multiple myeloma

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2195-2202 ◽  
Author(s):  
Masahiro Abe ◽  
Kenji Hiura ◽  
Javier Wilde ◽  
Keiji Moriyama ◽  
Toshihiro Hashimoto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Stromal Cells ◽  
Neutralizing Antibodies ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Abstract Multiple myeloma (MM) cells cause devastating bone destruction by activating osteoclasts in the bone marrow milieu. However, the mechanism of enhanced bone resorption in patients with myeloma is poorly understood. In the present study, we investigated a role of C-C chemokines, macrophage inflammatory protein (MIP)–1α and MIP-1β, in MM cell-induced osteolysis. These chemokines were produced and secreted by a majority of MM cell lines as well as primary MM cells from patients. Secretion of MIP-1α and MIP-1β correlated well with the ability of myeloma cells to enhance osteoclastic bone resorption both in vitro and in vivo as well as in MM patients. In osteoclastogenic cultures of rabbit bone cells, cocultures with myeloma cells as well as addition of myeloma cell-conditioned media enhanced both formation of osteoclastlike cells and resorption pits to an extent comparable to the effect of recombinant MIP-1α and MIP-1β. Importantly, these effects were mostly reversed by neutralizing antibodies against MIP-1α and MIP-1β, or their cognate receptor, CCR5, suggesting critical roles of these chemokines. We also demonstrated that stromal cells express CCR5 and that recombinant MIP-1α and MIP-1β induce expression of receptor activator of nuclear factor-κB (RANK) ligand by stromal cells, thereby stimulating osteoclast differentiation of preosteoclastic cells. These results suggest that MIP-1α and MIP-1β may be major osteoclast-activating factors produced by MM cells.

Inhibition of p38α MAPK Reduces Tumor Burden, Prevents the Development of Myeloma Bone Disease, and Increases Survival in the 5T2 and 5T33 Murine Models of Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3436-3436 ◽  
Author(s):  
Karin Vanderkerken ◽  
Satya Medicherla ◽  
Les Coulton ◽  
Benjamin Van Camp ◽  
Andy Protter ◽  
...  
Keyword(s):  
Bone Disease ◽  
Critical Role ◽  
Disease Free Survival ◽  
Myeloma Cell ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Growth And Survival ◽  
Myeloma Bone Disease ◽  
Osteolytic Bone Disease

Abstract The bone microenvironment plays a critical role in supporting the growth and survival of myeloma cells and the development of osteolytic bone disease. Signalling through p38 α MAPK mediates synthesis of myeloma cell survival factors by stromal cells; whereas, inhibiting p38 α MAPK reduces myeloma cell proliferation and inhibits osteoclast formation in vitro. However, it is unclear whether p38 α MAPK inhibition will prevent the growth and survival of myeloma cells and the bone disease in vivo. The aim of this study was to determine whether SCIO-469, a selective p38 α MAPK inhibitor, would inhibit myeloma growth and prevent the development of bone disease in the 5TMM syngeneic models of myeloma. Treatment of 5TMM cells, in vitro, with SCIO-469 resulted in a clear inhibition of p38 phosphorylation, as assessed by Western blotting and an inhibition up to 35% of stromal cell induced 5T33MM proliferation. Injection of 5T2MM murine myeloma cells into C57Bl/KaLwRij mice resulted in the growth of myeloma in bone and the development of bone disease characterized by increased osteoclast surface (p<0.05), a reduction in cancellous bone (p<0.01) and the presence of osteolytic bone lesions on x-ray (p<0.01). Treatment of 5T2MM-bearing mice with SCIO-469 (150mg/kg in the diet, therapeutical treatment from paraprotein detection) resulted in a 42% decrease in serum paraprotein and prevented development of osteolytic lesions (p<0.01). Injection of 5T33MM cells into C57Bl/KaLwRij mice also resulted in the development of myeloma but not associated bone disease. Treatment of 5T33MM-bearing mice from the time of tumor cell injection with SCIO-469 resulted in a decrease in serum paraprotein (8.8+/−1.4g/dl to 0.04+/− 0.03g/dl, p<0.001) and a reduction in the proportion of tumor cells in the bone marrow (67 +/− 8.1% to 1.09 +/− 0.58%, p<0.001). Kaplan-Meier analysis demonstrated an increase in disease-free survival (veh=27.5 days vs 96 days, p<0.001) after treatment of the mice with SCIO-469. These data demonstrate that targeting p38 α MAPK with SCIO-469 is associated with an anti-myeloma effect, which indirectly prevents the development of myeloma bone disease.

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&lt;0.0001) when compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p&lt;0.001). There was a strong correlation between bone lytic disease and serum CTX (r=0.59, p&lt;0.01), and sRANKL (r=0.4, p=0.03). Patients with severe bone disease (&gt;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&lt;0.001) after 4 cycles, which was still seen after 8 cycles of treatment (p&lt;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&lt;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.

Serum Concentrations of DKK-1 Correlate with the Extent of Bone Disease in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3518-3518
Author(s):  
Martin Kaiser ◽  
Maren Mieth ◽  
Peter Liebisch ◽  
Susanne Rötzer ◽  
Christian Jakob ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Conventional Radiography ◽  
Bone Lesions ◽  
X Rays ◽  
Myeloma Bone Disease ◽  
Lytic Lesions ◽  
Significant Difference ◽  
First Time

Abstract Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells was reported to cause inhibition of osteoblast precursors. DKK-1 is an inhibitor of the Wnt/β-catenin signaling, which is a critical signaling pathway for the differentiation of mesenchymal stem cells into osteoblasts. So far there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. Methods: DKK-1 serum levels were quantified in 184 previously untreated MM patients and 33 MGUS patients by ELISA, using a monoclonal anti-DKK-1 antibody. For the evaluation of bone disease, skeletal X-rays were performed. Results: Serum DKK-1 was elevated in MM as compared to MGUS (mean 11,963 pg/mL versus 1993 pg/mL, P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL versus 15,209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL versus 17,915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: mean 3114 pg/mL vs. 3559 pg/mL vs. 24,068 pg/mL; P = 0.002). Conclusion: This is the largest study of DKK-1 serum levels in multiple myeloma patients and data show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, suggesting that DKK1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

Developing In Vivo Model for Studying Mechanisms of Osteoblast Suppression in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4731-4731
Author(s):  
Chang-Sook Hong ◽  
Alisa Huston ◽  
Flavia Esteve ◽  
Judy Anderson ◽  
Ken Patrene ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Osteoblast Differentiation ◽  
Treated Group ◽  
Bone Lesions ◽  
Neoplastic Disease ◽  
In Vivo Models ◽  
Myeloma Cells ◽  
Ganciclovir Treatment

Abstract Multiple myeloma (MM) is an incurable neoplastic disease characterized by an accumulation of plasma cells in bone marrow. Osteolytic bone lesions are the major source of morbidity in MM patients and are associated with bone pain and fractures and hypercalcemia. The bone lesions result from increased osteoclastic bone destruction in areas adjacent to the myeloma cells. New bone formation that normally happens at sites of previous bone resorption still occurs in early stages of the disease but is absent in advanced MM. Although the molecular basis for the increased osteoclastic activity has been intensely investigated, the basis for the decreased osteoblast activity is just beginning to be understood. Recently, inhibitors of WNT signaling pathway, Dickkorpf1 (DKK1) and secreted Frizzle-Related Protein-2 (sFRP2) have been identified as factors involved in osteoblast suppression in MM. In addition, IL-3 and IL-7 are increased in plasma of MM patients and suppress osteoblastogenesis in cell culture models. However, the role of those factors in the osteoblastic activity in MM patients is unclear. Studies in patients are confounded by cytotoxic therapy as well as bisphosphonates, which are standard therapy for MM patients. Therefore, preclinical in vivo models are required to delineate the mechanisms responsible for the profound osteoblast suppression in MM. We have developed a mouse model of myeloma bone disease in which genetically modified myeloma cells can be selectively ablated without the confounding effects of cytotoxic therapies and allows us to tract the growth of MM cells. The 5TGM1 cell line which is the most common version of murine MM, was stably transfected with the thymidine kinase (TK) gene from herpes simplex virus, which permits eradication of myeloma cells with ganciclovir, as well as GFP and luciferase genes to detect the presence of MM cells. One ug/ml ganciclovir treatment in culture results in 100% death of the transfected 5TGM1 cells in 4 days. Importantly, ganciclovir treatment of primary marrow cell cultures had no effect on growth and differentiation of osteoblast and hematopoietic progentitors. Co-culturing of primary marrow cells with 5TGM1 expressing TK has no bystander effect on osteoblast differentiation with ganciclovir treatment. Subcutaneously implanted 5TGM1 cells into SCID mice were eradicated by intraperitoneal injection of 20mg/kg ganciclovir/d for 2 weeks. The dose of ganciclovir did not affect osteoblast differentiation of primary marrow culture from the mice treated with ganciclovir. Then we injected the 5TGM1 cells into tibia of SCID nude mice (n=4 per group). After measuring the increase of serum IgG2b level, half of the mice were treated with ganciclovir for 2 weeks and the other with saline. Our preliminary data show that osteogenic cultures of bone marrow from the ganciclovir treated mice had significantly higher alkaline phosphatase activity than cultures derived from the saline treated group (p=0.03). In addition, the ganciclovir treated mice had tendency of higher trabecular bone volume than the saline-treated group (p=0.08). These results demonstrate that this model should be useful for studying mechanisms of osteoblast suppression in MM.

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