Dear Label_Name,

Greetings! I hope you are well.

I am writing on behalf of an international publishing house, Science and Education Publishing, USA (http://www.sciepub.com).

Science and Education Publishing (SciEP) is a multidisciplinary open access publisher of Journals covering the fields of Science, Technology and Medicine. All SciEP publications are subject to high-quality peer review, editorial and production processes and are freely available online.

Welcome to the April, 2013 edition of SciEP newsletter, providing monthly summaries of articles on science & education related topics of interest to scientist and professionals. The mission of our journals is to provide an open access forum for publishing new findings on issues pertinent to scientific and academic field. We also invite you to submit original research papers, review articles, short reports, or case studies are considered for publication in our Multidisciplinary Journals.

American Journal of Public Health Research
DOI: 10.12691/ajphr-1-1-3

The Implementation of a Tele-Homecare System with Service Oriented Architecture and HL7 Message Transmission Standard
Ching-Sung Wang

American Journal of Medical and Biological Research
DOI: 10.12691/ajmbr-1-1-2

The Influence of Ethanol on Pyruvate Kinases Activity in Vivo, in Vitro, in Silico
Lelevich Sergey Vladimirovich, Khrustalev Vladislav Victorovich, Barkovsky Eugene Victorovich, Shedogubova Tatyana Aleksandrovna

American Journal of Medical Sciences and Medicine
DOI: 10.12691/ajmsm-1-1-1

Clinical and Histological Features in Wegener Granulomatosis
Li Cavoli Gioacchino, Passantino Rita, Bono Luisa, Tortorici Calogera, Ferrantelli Angelo, Giammarresi Carlo, Rotolo Ugo

American Journal of Infectious Diseases and Microbiology
DOI: 10.12691/ajidm-1-1-2

The Curse of Lymphatic Filariasis: Would the Continual Use of Diethylcarbamazine Eliminate this Scourge in Papua New Guinea?
Anne Lanham, Lillian Mwanri

We have released issues of some journals on February 2013.
American Journal of Public Health Research
American Journal of Medical Sciences and Medicine
American Journal of Medical and Biological Research
American Journal of Pharmacological Sciences
American Journal of Clinical Medicine Research
American Journal of Nursing Research
American Journal of Cancer Prevention
American Journal of Medicine Studies
American Journal of Infectious Diseases and Microbiology
American Journal of Cardiovascular Disease Research
American Journal of Biomedical Research
American Journal of Mechanical Engineering
American Journal of Microbiological Research
Journal of Preventive Medicine
American Journal of Food and Nutrition
American Journal of Hypertension Research
American Journal of Sports Science and Medicine
Journal of Cancer Research and Treatment
American Journal of Zoological Research
Journal of Biomedical Engineering and Technology
American Journal of Microbiological Research
Biomedical Science and Engineering

We are pleased to announce that submissions are now being accepted for peer review for all the journals across all our subject areas in SciEP.

Please submit your manuscript via our online submission system:
http://www.sciepub.com/author/signin

To unsubscribe from our mailing list, please click on the following link: unsubscribe

I am looking forward to hearing from you.

Kind regards,

David Rain
Email:join@sciepub.com
Science and Education Publishing (http://www.sciepub.com)

Bone Targeted Therapy in Multiple Myeloma

Hiroko Nishida

Department of Pathology, Keio University, School of Medicine, Tokyo, Japan

Abstract: The interaction between multiple myeloma (MM) cells and cellular components and its (BM) microenvironment promotes MM cell growth and osteolytic bone destruction. Osteolytic bone disease, characterized by bone pain, increased risk of pathologic fractures, tumor-induced hypercalcemia, is a frequent complication of MM patients. These skeletal-related events (SREs) decrease their quality of life and reduce their survival. Therefore, therapeutic strategies targeting the interplay between MM cells and the BM cellular components, including osteoclasts (OCs), stromal cells as well as MM cells themselves are necessary not only to attain tumor regression but to reduce its associated bone disease. The goal of bone-targeted therapy in MM is to reduce or delay the incidence of SREs and to improve the quality of life in affected patients. Currently, several novel agents are in the clinical trials.

Keywords: multiple myeloma, bone marrow microenvironment, osteoclast, skeletal-related events, bone-targeted therapy

Citation: Hiroko Nishida, Bone Targeted Therapy in Multiple Myeloma. International Journal of Hematological Disorders, 3 (1). 3-6. January 2017. doi:10.12691/ijhd-3-1-2

1. Introduction

The bone is a common site of metastasis in patients with advanced cancer such as breast cancer, lung cancer, prostate cancer, osteosarcoma and multiple myeloma (MM) [1,2,3]. MM is hematological malignancy, characterized by the accumulation of monoclonal plasma cells in the bone marrow (BM). In the BM microenvironment of MM, the cellular interaction promotes MM cell growth and devastates its associated osteolytic bone disease, characterized by bone pain, increased risk of bone fracture, which leads to the skeletal related events (SREs). The frequency of SREs depends on the characteristics of bone lesions, locations, the number of lesions, or the treatment complications and its occurrence is reported to be about 85-90% of MM patients [4,5]. Moreover, their severity depends on MM disease activity and high risk MM results in decreased quality of life and poor prognosis. MM cells promote osteoclast (OC) formation in association with BM stromal cells, whereas inhibits osteoblast (OB) formation, leading to the bone destruction. OCs, BM stromal cells (BMSCs) and endothelial cells supply a microenvironment, suitable for MM cell expansion. Thus, the interaction between MM cells and cellular components in the BM leads to the vicious cycle to expand MM cells and destructive bone lesions [6,7,8]. Therefore, novel therapeutic strategies targeting the interaction between MM cells and BM microenvironment is necessary not only to attain tumor regression but also to reduce bone destruction and improve patient outcome [9,10].

This review focuses on the mechanism of the interaction between MM cells and their surrounding cells in the BM microenvironment of MM and assesses bone targeted therapy to treat its associated bone disease to prevent the occurrence of SREs and tumor progression in affected patients [10]. In addition, several potential novel therapeutic strategies will be also discussed for the purpose of providing clues further to develop novel therapeutic approach to improve the survival and quality or life of MM patients.

2. The Mechanism of Bone Disease in MM

The interaction between MM cells and BM microenvironment plays an important role in the pathogenesis of MM. Soluble factors or physical contacts within the cellular components of BM microenvironment promote MM cell growth, survival and drug resistance. It is composed of various kinds of cellular components, including BM stromal cells (SCs), vascular endothelial cells, osteocytes, and OCs with decreased OBs.

BMSCs induces various cytokines or growth factors, such as interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), stromal cell-derived factor 1α (SDF1α), insulin-like growth factor 1 (IGF1) as well as physically contact with MM cells for MM cell proliferation [11,12,13]. They simultaneously secrete RANKL to enhance osteoclastgenesis in MM. RANKL enhances OC apoptosis and leads to decrease the production of osteoprotegerin (OPG), a decay receptor for RANKL, which inhibits RANKL-RANK signaling [14]. The marked imbalance exists between RANKL and OPG levels in the BM microenvironment of MM and it promotes OC activation. Vascular cell adhesion molecule 1 (VCAM-1) expressed on BMSCs binds to very late antigen 4 (VLA-4) on MM cells. Its interaction upregulates RANKL but downregulates OPG in BMSCs and induces osteoclastgenesis [15]. It also increases the secretion of chemokines such as MIP1α and MIP1β by MM cells, which acts on monocytic progeniters and stimulate osteoclastgenesis [16].

Osteoclastgenesis is enhanced in the BM of MM. Factors produced by MM cells including RANKL, MIP1α, Interleukin-3 (IL-3) enhance bone destruction and suppress bone formation. Tumor necrosis factor α (TNFα), stromal cell-derived factor 1α (SDF1α), insulin-like growth factor 1 (IGF1), a proliferation inducing ligand (APRIL) and B cell activating factor (BAFF), secreted by OCs play an important role in MM cell growth. MM cells and OCs also contact directly [16,17,18,19]. These cells promote their growth each other and form a vicious cycle to lead to MM cell expansion and extensive bone destruction.

Angiogenesis is enhanced in the BM of MM. MM cells and BMSCs secrete angiogenetic factors such as VEGF, basic fibroblast growth factor (bFGF) [13,20]. Endothelial cells express VEGF receptor which interacts with αvβ₃ integrin. OCs secrete osteopontin, a ligand of αvβ3 integrin, which acts on endothelial cells with VEGF, secreted by MM cells and enhance angionegesis. MMP-9, produced by OCs is also involved in angiogenesis and enhances osteoclastgenesis [21]. MM cells and various cells including OCs and endothelial cells in the BM microenvironment are closely related to tumor progression, bone destruction and angiogenesis in MM.

Osteoblastic differentiation inhibits MM cell growth as well as restores bone formation in MM bone lesions. However, the inhibition of osteoblastic formation was observed in MM. The WNT signaling pathway plays an important role in OB differentiation and its functions. DKK1 is a soluble inhibitor of the WNT pathway and is upregulated in MM cells and is more intensely expressed in MM patients with more severe lytic bone distruction, suggesting a role of DKK1 in MM bone disease [22,23,24]. DKK1 increases RANKL and decrease OPG, secreted by OBs. Thus, it induces osteoclastgenesis and inhibits osteoblastgenesis in MM and its suppression results in bone loss.

3. Bone Targeting Therapy in MM

MM is incurable disease with novel anti-tumor agents including immunotherapy or high-dose chemotherapy with stem cell transplantation. Patients with MM frequently experience pathological fractures, spinal cord compression or hypercalcemia, known as SREs, which lead to pain and a decreased quality of life [4,5,7,8]. Current therapeutic options of MM-associated bone disease include intraveneous bisphosphonates, surgical procedures, radiotherapy and the treatments towards MM itself.

Bisphosphonates are currently administrated as the part of the treatments in MM with anti-tumor agents to delay or prevent the occurrence of SREs and hypercalcemia [25,26,27,28]. They also increase the apoptosis of MM cells. The mechanism of action is to keep high affinity for bone mineral through their similarity to pyrophosphates. Nitrogen containing bisphosphonates such as zoledronic acid and pamidronates suppress farnesyl pyrophosphate synthetase (FPPS), the enzyme in the mevalonate pathway. Moreover, they block prenylate GTPase signaling and induce OC apoptosis. In addition, they have anti-angiogenetic effects via inhibiting the expression of VEGF or platelet derived growth factor (PDGF) in endothelial cells. It was also demonstrated that bisphosphonates inhibit tumor cell adhesion to the extracellular matrix and prevent invasion or metastasis in solid tumors [25,26,27,28]. Recent reports suggest that zoledronic acid has been to be effective in prolonging time to the first SRE in advanced cancer and bone metastasis [29,30,31].Rosen et al. demonstrated that compared with pamidronate, zoledronic acid (4mg) was shown to be reduce overall risk of developing skeletal complications including hypercalcemia by an additional 16 % in patients (n=1648) with bone lesions with MM or advanced breast carcinoma [26,27]. However, in other cases, SREs still occur after the treatment with zoledronic acid. Moreover, renal dysfunction frequently occurs in patients with MM and zoledronic acid exacerbate their renal impairment [32]. It also causes the osteonecrosis of the jaw (ONJ) [33]. Therefore, in several cases, alternative therapeutic approach is needed, further to reduce the occurrence of SREs without these drug toxicities.

Recently, several clinical trials have demonstrated that anti-RANKL monoclonal antibody, denosumab can significantly reduce SREs associated with osteolytic metastatic cancers [34]. Denosumab is a fully human monoclonal antibody which binds RANKL with high specificity and inhibit RANKL-RANK signaling and suppress OC activity, which leads to reduced bone resorption and the incidence of SREs caused by the bone destruction. Several trials showed that denosumab was superior to zoledronic acid in delaying or preventing the occurrence of SREs in metastatic breast cancer [35,36,37]. Initial dose adjustments of zoledronic acid is necessary for patients who had baseline creatinine clearance lower than 60mL/min. In contrast, dose adjustments or dose withholding for renal function are not required for denosumab. Henry et al. demonstrated that in patients with a baseline creatinine clearance lower than 60 ml/min, renal adverse effects occurred in 21.6% of patients receiving zoledronic acid, compared with 11.3% receiving denosumab [41]. Changes in serum calcium was occurred because of the mechanism of action of denosumab. Hypocalcemia was seen more frequently with denosumab than with zoledronic acid. However, it is manageable with appropriate supplementation with oral calcium and vitamin D [35,38,41]. Denosumab has an efficacy with little toxicities, but not be superior to zoledronic acid in patients with bone metastasis of other advanced cancer or MM [35-41]. Moreover, it does not significantly decrease tumor burden in MM [37,41].

A RANKL inhibitor, RANKL-Fc decreases bone resorption induced by RANKL as well as reduces tumor burden in animal models of MM [42]. Antagonists to MIP-1α receptor, CCR1 blocks OC formation and inhibits the adhesion between MM cells and BMSCs [43]. Several novel anti-tumor agents including proteasome inhibitors inhibits OC differentiation via the blockade of NFκB signaling pathway [44,45].

CD26 is expressed in normal OCs and is intensely expressed in OCs in osteolytic bone metastasis including breast cancer, osteosarcoma, adenocarcinoma such as lung cancer, and MM [46]. Humanized anti-CD26 monoclonal antibody blocks OC differentiation in vitro during the early phase of human OC development via the blockade of MKK3/6-p38MAPK-mi/Mitf signaling pathway in OC precursor cells. Therefore, anti-CD26 antibody may have therapeutic potential for the treatment of osteolytic lesions following metastasis including MM to alleviate bone destruction and reduce the occurrence of total SREs [46].

Anti-DKK1 monoclonal antibody enhances osteoblastic differentiation and currently used in clinical trials and attains the promising results in MM bone disease [47,48]. Transforming growth factorβ(TGFβ) secreted by OBs and osteotcytes inhibits terminal OB differentiation and minerarlization [49]. TGFβ level is high in the bone lesions of MM and is involved in the bone remodeling. Activin A inhibitor, TGFβinhibitor induces OB differentiation and leads to decrease destructive bone lesions and tumor progression [50].

4. Future Directions

In addition to anti-tumor agents for MM cells, novel agents targeting osteolytic bone lesions seem to be promising therapeutic strategies to delay or prevent SREs for the treatment of MM. Further study of the molecular mechanism of cellular interactions in the BM microenvironment of MM will provide us with novel therapeutic approaches which have dramatic effects on MM-associated bone disease as well as MM cell expansion.

5. Conclusions

MM cells and cellular components interact closely with each other in the BM microenvironment of MM. Bone-targeted therapy is important therapeutic strategies in combination with cytotoxic agents for the treatment of MM. Further studies elucidating the mechanism responsible for the increased OC activity and decreased OC activity in MM will lead to the development of novel therapeutic targets to treat both bone destruction and MM progression.

References

[1]   | Giuliani N, Colla S, Rizzoli V. New insight in the mechanism of osteoclast activation and formation in multiple myeloma: focus on the receptor activator of NF-kappaB ligand (RANKL). Exp Hematol. 2004; 32(8): 685-91.
[2]   | Yaccoby S, Wezeman MJ, Henderson A, et. al. Cancer and the microenvironment: myeloma-osteoclast interactions as a model. Cancer Res. 2004; 64(6): 2016-23.
[3]   | Dougall WC. Molecular pathways: osteoclast-dependent and osteoclast-independent roles of the RANKL/RANK/OPG pathway in tumorigenesis and metastasis. Clin Cancer Res. 2012; 18(2): 326-35.
[4]   | Callander NS, Roodman GD. Myeloma bone disease. Semin Hematol. 2001; (38): 276-85.
[5]   | Melton LJ, Kyle RA, Achenbach SJ, et al. Fracture risk with multiple myeloma: a population-based study. J Bone Miner Res. 2005; 20: 487-93.
[6]   | Abe M, Hiura K, Wilde J, yet al. Osteoclasts enhance myeloma cell growth and survival via cell-cell contact: a vicious cycle between bone destruction and myeloma expansion. Blood. 2004; 104: 2484-91.
[7]   | Silbermann R, Roodman GD. Myeloma bone disease: Pathophysiology and management. 2013; 12(2): 59-69.
[8]   | Roodman GD. Pathogenesis of myeloma bone disease. Leukemia. 2009; 23: 435(3)-41.
[9]   | Roodman GD. Targeting the bone microenvironment in multiple myeloma. J Bone Miner Metab. 2010; 28(3): 244-50.
[10]   | Hideshima T, Mitsiades C, Tonon G, et al. Understandimng multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targetes. Nat Rev Cancer. 2007; 7(8): 585-98.
[11]   | Wada T, Nakashima T, Hiroshi N, et al. RANKL-RANK signaling in osteoclastgenesis and bone disease. Trends Mol Med. 2006; 12: 17-25.
[12]   | Zannettino AC, Farrugia AN, Kortesidis A, et al. Elevated serum levels of stromal-derived factor-1alpha are associated with increased osteoclast activity and osteolytic bone disease in multiple myeloma patients. Cancer Res. 2005; 65(5): 1700-9.
[13]   | Tanaka Y, Abe M, Hiasa M, Oda A, et al. Myeloma cell-osteoclast interaction enhances angiogenesis together with bone resorption: a role for vascular endothelial cell growth with bone resorption: a role for vascular endothelial growth factor and osteopontin. Clin Cancer Res. 2007; 13(3): 816-23.
[14]   | Sezer O, Heider U, Zavrski I, et al. RANK ligand and osteoproteogerin in multiple myeloma bone disease. Blood. 2003; 101(6): 2094-8.
[15]   | Abe M, Hiura K, Ozaki S, et al. Vicious cycle between myeloma cell binding to bone marrow stromal cells via VLA4-VCAM-1 adhesion and macrophage inflammatory protein-1alpha and MIP-1beta production. J Bone Miner Metab. 2009; 27(1): 16-23.
[16]   | Choi SJ, Cruz JC, Craig F, et al. Macrophage inflammatory protein 1-alpha is a potential osteoclast stimulatory factor in multiple myeloma. 2000; 96(2): 671-5.
[17]   | Lee JW, Chung HY, Ehrlich LA, et al. IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. Blood. 20004; 103(6): 2308-15.
[18]   | Moreaux J, Legouffe E, Jourdan E. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood. 2004; 103(8): 3148-57.
[19]   | Tai YT, Li X, Breitkreutz I, et al. Role of B-cell-activating actor in adhesion and growth of human myeloma cells in the bone marrow microenvironment. Can Res. 2006; 66(13): 6675-82.
[20]   | Jakob C, Sterz J, Zavrski I, et al. Angiogenesis in multiple myeloma. Eur J Cancer. 2006; 42(11): 1581-90.
[21]   | Cackowski FC, Anderson JL, Patrene KD, et al. Osteoclasts are important for bone angiogenesis. Blood. 2009; 115(1): 140-9.
[22]   | Gunn WG, Conley A, Deininger L, et al. A crosstalk between myeloma cells and marrow stromal cells stimulates production of DKK1 and interleukin-6: a potential role in the development of lytic bone disease and tumor progression in multiple myeloma. Stem Cells. 2006; 24(4): 986-91.
[23]   | Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist against DKK1 in the development of osteolytic lesions in multiple myeloma. N Eng J Med. 2003. 349(26); 2483-94.
[24]   | Giuliani N, Rizzoli V. Myeloma cells and bone marrow osteoblast interactions: role in the development of osteolytic lesions in multiple myeloma. Leuk Lymphoma. 2007; 48(12): 2323-9.
[25]   | Terpos E, Roodman GD. Dimopoulos MA. Optimal use of bisphosphonates in patients with multiple myeloma. Blood. 2013; 121(17): 3325-8.
[26]   | Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesion of multiple myeloma. A phase III, double-blind, comparative trial. Cancer J. 2001; 7(5): 377-87.

[27]  
Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications with advanced multiple myeloma or breast carcinoma: A randomized, double-blind multicenter, comparative trial. Cancer. 2003; 98(8): 1735-44.

[28]   | Saad F, Chen YM, Gleason DM, et al. Continuing benefit of zoledronic acid in preventing skeletal complications in patients with bone metastases. Clin Genitourin Cancer. 2007; 56(6): 390-6.
[29]   | Rosen LS, Gordon D, Tchekmedyian NS, et al. Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non small cell lung cancer and other solid tumors: A randomized, Phase III, double-blind, placebo-controlled trial. Cancer. 2004; 100(12): 2613-21.
[30]   | Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial o zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002; 94(19): 1458-68.
[31]   | Kohno N, Aogi K, Minami H, et al. Zoredronic acid significantly reduces skeletal complications compared with placebo in Japanese woman with bone metastases from breast cancer: A randomized, placebo-controlled trial. J Clini Oncol. 2005; 23(15): 3314-21.
[32]   | Chang JT, Green L, Beitz J, et al. Renal failure with the use of zoredronic acid. N Eng J Med. 2003; 349(17): 1676-9.
[33]   | Walter C, Al-Nawas B, Frickhofen N, et al. Prevalence of bisphosphonates associated osteonecrosis of the jaws in multiple myeloma patients. Head Face Med. 2010;6:11.
[34]   | Castellano D, Sepulveda JM, Escobar IG, et al. The role of RANKL-ligand inhibition in cancer: the story of denosumab. The Oncologist. 2011, 16, 136-45.
[35]   | Stopeck AT, Lipton A, Body JJ, et al. Denosumab compared with zoledronic acid or the treatment of bone metastasis in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010; 28(35): 5132-9.
[36]   | Irelli A, Cocciolone V, Cannita K et al. Bone targeted therapy for preventing skeletal-related events in metastatic breast cancer. Bone. 2016; 87: 169-175.
[37]   | Body JJ, Facon T, Coleman RE, et l. A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res. 2006;12(4): 1221-8.
[38]   | Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for the treatment of bone metastases in men with castration-resistant prostate cancer: a randomized, double-blind study. Lancet. 2011; 377(9768): 813-22.
[39]   | Hutton B, Morretto P, Emmenegger U, et al. Bone-targeted agenet use for bone metastases from breast cancer and prostate cancer: A patient survey. J Bone Oncol. 2013; 2(3): 105-9.
[40]   | LeVasseur N, Clemons M, Huttom B, et al. Bone-targeted therapy use in patients with bone metastases from lung cancer: A systemic review of randomized controlled trials. Cancer Treat Rev. 2016; 50: 183-93.
[41]   | Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastasis in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011. 29(9), 1125-32.
[42]   | Croucher PI, Shipman CM, Lippitt J, et al. Osteoprotegrin inhibits the development of osteolytic bone disease in multiple myeloma. Blood. 2001;98(13):3534-40.
[43]   | Vallet S, Raje N, Ishitsuka K, et al. MLN3897, a novel CCR1 inhibitor, impairs osteoclastgenesis and inhibits the interaction of multiple myeloma and osteoclasts. Blood. 2007; 110(10): 3744-52.
[44]   | Von Metzler I, Krebbel H, Hecht M, et al. Bortezomib inhibits human osteoclastgenesis. Leukemia. 2007; 21(9): 2025-34.
[45]   | Giuliani N, Morandi F, Tagliferri S, et al. The proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple myeloma patients. Blood. 2007; 110(1): 334-8.
[46]   | Nishida H, Suzuki H, Madokoro H, et. Al. Blockade of CD26 signaling inhibits human osteoclast development. J Bone Miner Res. 2014, 29(11) 2439-55.
[47]   | Heath DJ, Chantry AD, Buckle CH, et al. Inhibiting dickkopf-1 (Dkk1) removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma. J Bone Miner Res. 2009; 24(3): 425-36.
[48]   | Fulcininti M, Tassone P, Hideshima T, et al. Anti-DKK1 mab(BHQ) as apotential therapeutic agent for multiple myeloma. Blood. 2009; 14(2): 371-9.
[49]   | Takeuchi K, Abe M, Hiasa M, et al. TGF-beta inhibition restores terminal osteoblast differentiation to suppress myeloma growth. PLoS One. 2010; 5: e9870.
[50]   | Vallet S, Mukherjee S, Vaghela N, et al. Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease. Proc Natl Acad Sci USA. 2010; 107(11): 5124-9.