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.

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 Anti-Müllerian Hormone Negatively Regulates Osteoclast Differentiation by Suppressing the Receptor Activator of Nuclear Factor-κB Ligand Pathway

2021 ◽  
Vol 28 (3) ◽  
pp. 223-230
Author(s):  
Jung Ha Kim ◽  
Yong Ryoul Yang ◽  
Ki-Sun Kwon ◽  
Nacksung Kim
Keyword(s):  
Osteoblast Differentiation ◽  
Bone Cells ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Bone Morphogenetic Protein 2 ◽  
Tartrate Resistant Acid Phosphatase ◽  
Nuclear Factor ◽  
Bone Homeostasis ◽  
Alizarin Red ◽  
Receptor Activator

Background: Multiple members of the transforming growth factor-β (TGF-β) superfamily have well-established roles in bone homeostasis. Anti-Müllerian hormone (AMH) is a member of TGF-β superfamily of glycoproteins that is responsible for the regression of fetal Müllerian ducts and the transcription inhibition of gonadal steroidogenic enzymes. However, the involvement of AMH in bone remodeling is unknown. Therefore, we investigated whether AMH has an effect on bone cells as other TGF-β superfamily members do.Methods: To identify the roles of AMH in bone cells, we administered AMH during osteoblast and osteoclast differentiation, cultured the cells, and then stained the cultured cells with Alizarin red and tartrate-resistant acid phosphatase, respectively. We analyzed the expression of osteoblast- or osteoclast-related genes using real-time polymerase chain reaction and western blot.Results: AMH does not affect bone morphogenetic protein 2-mediated osteoblast differentiation but inhibits receptor activator of nuclear factor-κB (NF-κB) ligand-induced osteoclast differentiation. The inhibitory effect of AMH on osteoclast differentiation is mediated by IκB-NF-κB signaling.Conclusions: AMH negatively regulates osteoclast differentiation without affecting osteoblast differentiation.

scholarly journals The Src Inhibitor AZD0530 Prevents the Development of Osteolytic Bone Disease in Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3018-3018
Author(s):  
Roy Heusschen ◽  
Joséphine Muller ◽  
Marilène Binsfeld ◽  
Erwan Plougonven ◽  
Nadia Mahli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Disease Stage ◽  
Bone Lesions ◽  
Mrna Levels ◽  
Osteoblast Function ◽  
Src Inhibitor ◽  
Osteolytic Bone Disease

Abstract Destructive bone lesions due to osteolytic bone disease are a major cause of morbidity and mortality in multiple myeloma patients, occurring in more than 80% of cases. Underlying osteolytic bone disease is an uncoupling of the bone remodeling process, with an increased activity of osteoclasts and a decreased activity of osteoblasts. Current strategies to treat osteolytic bone disease focus on anti-resorptive agents, which do not rebuild bone loss. Src kinase has been implicated in both osteoclast and osteoblast function. In this study, we assessed the effect of Src inhibition with AZD0530 (saracatinib, Astra Zeneca) on the development of multiple myeloma and its associated osteolytic bone disease. We first determined Src family kinase expression in the multiple myeloma microenvironment and found that patient-derived myeloma cells express Src at low levels but disease stage does not correlate with Src expression levels. In accordance with the literature, Src mRNA expression was found to increase during osteoclast differentiation and decrease during osteoblast differentiation in publicly available microarray datasets. Next, we validated an inhibitory role of AZD0530 on osteoclast differentiation and function. At a pharmacological relevant concentration of 1 micromolar, AZD0530 inhibited the differentiation of RAW264.7 osteoclasts (Oc.N/FOV: 15.5+-1.6 treated vs. 53+-1.5 non-treated). AZD0530 treatment appeared to hamper efficient progenitor cell fusion and osteoclast polarization, reflected by a decrease of CTSK and DC-STAMP mRNA levels and a defective actin ring formation in treated cultures, which culminated in a complete inhibition of bone resorption. When assessing the effect of AZD0530 on osteoblast function we found that AZD0530 inhibits osteoblast differentiation, with a decreased expression of OSX and OCN, and alters osteoblast morphology. In vivo, AZD0530 did not alter myeloma cell bone marrow infiltration in both the 5TGM.1 (37+-6.3% AZD0530 treated vs. 25.2+-6.7% non-treated) and 5T2MM (26.1+-7.7% vs. 29.1+-6.4%) murine multiple myeloma models. However, bone health was significantly improved in both models following treatment with AZD0530. In the 5TGM.1 model multiple trabecular bone parameters were restored to levels observed in healthy control mice following AZD0530 treatment, including BV/TV (11.7+-0.3% treated vs. 6.4+-0.3% non-treated), Tb.N. (2.5+-6x10^-2/mm vs. 1.7+-9x10^-2/mm) and Tb.Th (46.2+-1micron vs. 37+-0.8micron). These results were confirmed in the 5T2MM model, which displays a more severe osteolytic bone disease. In addition, AZD0530 treatment resulted in an increase in cortical thickness (157.8+-0.8micron treated vs. 151.4+-0.7micron non-treated) and a decrease in the number and size of cortical lesions in 5TGM.1 mice. Finally, our findings were corroborated by histomorphometric analyses. In conclusion, we report a potent inhibitory effect of the Src inhibitor AZD0530 on the development of osteolytic bone disease in multiple myeloma. Our results indicate that AZD0530 exerts this effect via the modulation of both osteoclast and osteoblast function. These findings warrant further study of the feasibility and efficacy of AZD0530 to treat osteolytic bone disease in multiple myeloma patients. Disclosures No relevant conflicts of interest to declare.

Treatment of Bortezomib Increases Osteoblast Function in Patients with Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3457-3457 ◽  
Author(s):  
Ulrike Heider ◽  
Martin Kaiser ◽  
Christian Müller ◽  
Carsten-Oliver Schulz ◽  
Christian Jakob ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Clinical Evidence ◽  
Proteasome Inhibitors ◽  
Proteasome Inhibition ◽  
Serum Levels ◽  
Myeloma Bone Disease ◽  
Osteoblast Function ◽  
Osteoblast Activity ◽  
Osteoblast Markers

Abstract Myeloma bone disease is caused by an enhanced osteoclast activation and impaired osteoblast function. Until now, there is no specific treatment to restore osteoblast activity, and anti-myeloma therapies that lead to a disease remission are usually not associated with an increase of osteoblast markers. Recently, preclinical data suggested that proteasome inhibitors may enhance osteoblast function. Bortezomib (Velcade) represents the first substance from this group which is clinically used in relapsed multiple myeloma. To evaluate whether there is clinical evidence for an osteoblast stimulation under bortezomib treatment, we analyzed serum levels of two specific osteoblast markers, i.e. bone-specific alkaline phosphatase (BAP) and osteocalcin, in 25 multiple myeloma patients treated with bortezomib alone or in combination with dexamethasone. 56 percent of patients achieved a complete or partial remission. In the whole group of patients, mean serum levels of osteocalcin significantly increased from 6.3 μg/l before treatment to 10.8 μg/l after three months of therapy (P=0.024). In parallel, mean levels of BAP increased from 19.7 U/l to 30.2 U/l (P<0.0005). The increase in BAP was irrespective of the combination with dexamethasone and was noted both in responders and in non-responders. This is of special interest, since it implicates that the increase in osteoblast function may be a direct effect of bortezomib on osteoblasts and not an indirect consequence of the reduced myeloma burden. Proteasome inhibition may modulate the Wnt/b-catenin pathway, a major signalling pathway in osteoblasts. Myeloma patients with osteolytic lesions have been shown to overexpress DKK-1, an inhibitor of the Wnt/b-catenin pathway. Recent experiments on mesenchymal cells showed that proteasome inhibitors decreased the DKK-1 production. Moreover, proteasome inhibition elevates cytoplasmatic b-catenin levels by inhibition of its degradation. In addition, animal models gave evidence that proteasome inhibitors stimulate the bone morphogenetic protein (BMP)-2 mediated osteoblast differentiation. Taken together, these preclinical observations suggest that proteasome inhibition may enhance osteoblast activity. Our study gives clinical evidence for a significant improvement of osteoblast function under bortezomib. This is of special interest, since it demonstrates additional effects of proteasome inhibitors and may provide a novel treatment approach in myeloma bone disease.

scholarly journals Identifying genes that regulate bone remodeling as potential therapeutic targets

2005 ◽  
Vol 201 (6) ◽  
pp. 841-843 ◽  
Author(s):  
Stephen M. Krane
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Bone Remodeling ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Protein Signaling ◽  
Coupled Process ◽  
Systemic Factors ◽  
And Function ◽  
Deficient Mice

Bone remodeling, a coupled process involving bone resorption and formation, is initiated by mechanical signals and is controlled by local and systemic factors that regulate osteoblast and osteoclast differentiation and function. An excess of resorption over formation leads to the bone loss and increased propensity to fracture that is characteristic of osteoporosis. A newly described inhibitor of osteoblast differentiation, Ciz, interferes with bone morphogenic protein signaling. As a consequence, Ciz-deficient mice develop increased bone mass.

scholarly journals The Role of Proteasome Inhibitors in Multiple Myeloma Bone Disease and Bone Metastasis: Effects on Osteoblasts and Osteocytes

2021 ◽  
Vol 11 (10) ◽  
pp. 4642
Author(s):  
Denise Toscani ◽  
Luisa Craviotto ◽  
Nicola Giuliani
Keyword(s):  
Multiple Myeloma ◽  
Bone Metastasis ◽  
Bone Remodeling ◽  
Proteasome Inhibitors ◽  
Myeloma Bone Disease ◽  
Osteocyte Death ◽  
Multiple Alternative ◽  
Skeletal Related Events ◽  
Breast And Prostate Cancer

The alterations of bone remodeling are typical of multiple myeloma (MM) patients where the uncoupled and unbalanced bone remodeling caused the onset of osteolytic lesions. Moreover, bone metastasis occurs in the majority of patients with breast and prostate cancer. Skeletal-related events negatively impact on quality of life by increasing the vulnerability to fractures. Several bone-targeting treatments have been developed to control bone pain and pathological fractures, including bisphosphonates and Denosumab. Nevertheless, these agents act by inhibiting osteoclast activity but do not improve bone formation. Proteasome inhibitors (PIs) have shown bone anabolic effects and encouraging results in stimulating osteoblast differentiation and bone healing. Among these, the first-in-class bortezomib and the second-generation PIs, carfilzomib, and ixazomib regulate the bone remodeling process by controlling the degradation of several bone proteins. PIs have been recently proven to also be efficacious in blocking MM-induced osteocyte death providing new possible therapeutic use in the management of bone loss. PIs have significant side effects that limit their use as bone anabolic strategy. Multiple alternative approaches have been made. The conjugation of PIs with bisphosphonates, which can target them to bone, showed good results in terms of bone anabolic activity. However, the clinical implications of these effects require further investigations.

scholarly journals Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma

Blood ◽  
2008 ◽  
Vol 112 (1) ◽  
pp. 196-207 ◽  
Author(s):  
Ya-Wei Qiang ◽  
Yu Chen ◽  
Owen Stephens ◽  
Nathan Brown ◽  
Bangzheng Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Protein Production ◽  
Osteoclast Differentiation ◽  
Bone Lesions ◽  
Dependent Manner ◽  
Rankl Expression ◽  
Receptor Activator ◽  
Canonical Wnt ◽  
Dickkopf 1

Abstract Multiple myeloma (MM) is characterized by osteolytic bone lesions (OBL) that arise as a consequence of osteoblast inactivation and osteoclast activation adjacent to tumor foci within bone. Wnt signaling in osteoblasts regulates osteoclastogenesis through the differential activation and inactivation of Receptor Activator of Nuclear factor Kappa B Ligand (RANKL) and osteoprotegerin (OPG), positive and negative regulators of osteoclast differentiation, respectively. We demonstrate here that MM cell–derived DKK1, a soluble inhibitor of canonical Wnt signaling, disrupted Wnt3a-regulated OPG and RANKL expression in osteoblasts. Confirmed in multiple independent assays, we show that pretreatment with rDKK1 completely abolished Wnt3a-induced OPG mRNA and protein production by mouse and human osteoblasts. In addition, we show that Wnt3a-induced OPG expression was diminished in osteoblasts cocultured with a DKK1-expressing MM cell line or primary MM cells. Finally, we show that bone marrow sera from 21 MM patients significantly suppressed Wnt3a-induced OPG expression and enhanced RANKL expression in osteoblasts in a DKK1-dependent manner. These results suggest that DKK1 may play a key role in the development of MM-associated OBL by directly interrupting Wnt-regulated differentiation of osteoblasts and indirectly increasing osteoclastogenesis via a DKK1-mediated increase in RANKL-to-OPG ratios.

Multiple myeloma bone disease: pathophysiology of osteoblast inhibition

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 3992-3996 ◽  
Author(s):  
Nicola Giuliani ◽  
Vittorio Rizzoli ◽  
G. David Roodman
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Critical Role ◽  
High Capacity ◽  
Bone Destruction ◽  
Osteoclast Formation ◽  
Bone Lesions ◽  
Myeloma Bone Disease ◽  
Close Proximity ◽  
Cell Malignancy

Abstract Multiple myeloma (MM) is a plasma cell malignancy characterized by a high capacity to induce osteolytic bone lesions. Bone destruction in MM results from increased osteoclast formation and activity that occur in close proximity to myeloma cells. However, histomorphometric studies have demonstrated that MM patients with osteolytic bone lesions have lower numbers of osteoblasts and decreased bone formation. This impaired bone formation plays a critical role in the bone-destructive process. Recently, the biologic mechanisms involved in the osteoblast inhibition induced by MM cells have begun to be elucidated. In this article, the pathophysiology underlying osteoblast inhibition in MM is reviewed.

scholarly journals p53 functions as a negative regulator of osteoblastogenesis, osteoblast-dependent osteoclastogenesis, and bone remodeling

2005 ◽  
Vol 172 (1) ◽  
pp. 115-125 ◽  
Author(s):  
Xueying Wang ◽  
Hui-Yi Kua ◽  
Yuanyu Hu ◽  
Ke Guo ◽  
Qi Zeng ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Osteoblast Differentiation ◽  
Osteoclast Differentiation ◽  
Negative Regulator ◽  
High Bone Mass ◽  
Independent Manner ◽  
Interacting Protein ◽  
High Bone ◽  
Macrophage Colony ◽  
High Bone Mass Phenotype

p53 is a well known tumor suppressor. We show that p53 also regulates osteoblast differentiation, bone formation, and osteoblast-dependent osteoclast differentiation. Indeed, p53−/− mice display a high bone mass phenotype, and p53−/− osteoblasts show accelerated differentiation, secondary to an increase in expression of the osteoblast differentiation factor osterix, as a result. Reporter assays indicate that p53 represses osterix transcription by the minimal promoter in a DNA-binding–independent manner. In addition, p53−/− osteoblasts have an enhanced ability to favor osteoclast differentiation, in association with an increase in expression of macrophage-colony stimulating factor, which is under the control of osterix. Furthermore, inactivating p53 is sufficient to rescue the osteoblast differentiation defects observed in mice lacking c-Abl, a p53-interacting protein. Thus, these results identify p53 as a novel regulator of osteoblast differentiation, osteoblast-dependent osteoclastogenesis, and bone remodeling.

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