High Levels of Periostin in Patients with Multiple Myeloma Correlate with Low Bone Formation, Increased Fracture Rate and Diffuse MRI Pattern

2015 ◽  
Vol 15 ◽  
pp. e223-e224
Author(s):  
E. Terpos ◽  
D. Christoulas ◽  
E. Kastritis ◽  
T. Bagratuni ◽  
V. Koutoulidis ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Fracture Rate

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.

Diffuse MRI Pattern of Marrow Infiltration Correlates with Suppressed Bone Formation and Increased Incidence of Vertebral Fractures in Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5018-5018
Author(s):  
Evangelos Terpos ◽  
Lia A. Moulopoulos ◽  
Athanasios Anagnostopoulos ◽  
Efstathios Kastritis ◽  
Maria Roussou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Growth Factor ◽  
Bone Formation ◽  
Vertebral Fractures ◽  
Bone Marrow Involvement ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Bone Formation Markers ◽  
Tracp 5B ◽  
Focal Pattern

Abstract Bone lytic disease is a major feature of multiple myeloma (MM) and is characterized by an increased osteoclast activity which is accompanied by a suppressed osteoblast function. Furthermore, increased angiogenesis is implicated in the pathogenesis of both bone disease and myeloma cell growth and survival. Magnetic resonance imaging (MRI) pattern of bone marrow involvement correlate with prognosis in MM. The aim of this study was to evaluate the MRI pattern of marrow infiltration in correlation with markers of bone remodeling and angiogenesis in 44 newly diagnosed, untreated, MM patients (42 with symptomatic and 2 with asymptomatic MM). MRI of the spine was performed at the same time with measurement of a series of biochemical serum indices of bone metabolism and angiogenesis: osteoclast stimulators [soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and osteopontin], bone resorption markers [C- and N-telopeptide of collagen type-I (CTX, and NTX, respectively), and tartrate-resistant acid phosphatase isoform 5b (TRACP-5b)], bone formation markers [bone alkaline phosphatase (bALP), and osteocalcin (OC)], and angiogenic cytokines [vascular endothelial growth factor (VEGF), VEGF-A, angiogenin (ANG), angiopoietin-2 (ANGP-2), and basic fibroblast growth factor (bFGF)]. Myeloma patients had increased values of sRANKL (p<0.0001), OPG (p=0.01), sRANKL/OPG ratio (p<0.0001), NTX (p<0.0001), CTX (p=0.04), TRACP-5b (p<0.0001), VEGF (p=0.03), VEGF-A (p<0.0001), ANG (p<0.001), ANGP-2 (p=0.001), and bFGF (p=0.007) compared with respective values of 33, gender and age matched, controls. MRI revealed that 19 patients had focal pattern of marrow involvement, 11 diffuse, 10 normal, and 4 had a variegated pattern. Patients with diffuse MRI pattern also had reduced values of bALP (p<0.0001) compared to controls, while patients with normal pattern had reduced levels of both formation markers (OC and bALP; p=0.04 and <0.0001, respectively) and normal levels of OPG. On the contrary, patients with focal and variegated patterns had normal values of bALP and OC. Bone formation as assessed by bALP was more suppressed in patients with diffuse or normal MRI patterns compared to patients of focal or variegated patterns (mean±SD: 15.9±7.3 U/L vs. 29.3±24.5 U/L; p=0.02), while there was no difference between these groups in terms of resorption markers or osteoclast stimulators’ levels. In addition, patients with diffuse and normal MRI pattern also had increased levels of VEGF-A compared to patients of focal or variegated patterns (mean±SD: 83±68.4 pg/mL vs. 38.4±55 pg/mL; p=0.04). All but two patients of diffuse pattern (81%) had at least one vertebral fracture on radiographic evaluation of the axial skeleton compared to ten patients with focal pattern (52%). These results suggest that patients with diffuse MRI pattern have suppressed bone formation, increased levels of the major angiogenic cytokine VEGF-A, and increased incidence of vertebral fractures compared to patients who showed a focal pattern of myeloma infiltration.

High Dose Simvastatin Has No Beneficial Effect on Markers of Bone Turn-Over in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4824-4824
Author(s):  
Teis E. Sondergaard ◽  
Per T. Pedersen ◽  
Thomas L. Andersen ◽  
Thomas Lund ◽  
Patrick Garnero ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Pilot Study ◽  
Bone Resorption ◽  
Bone Formation ◽  
High Dose ◽  
Osteoclast Activity ◽  
Bone Formation Markers ◽  
Bone Degradation ◽  
Activity Trap

Abstract Background: Bone degradation in multiple myeloma (MM) is a result of increased bone degradation by osteoclasts that is not compensated for by bone forming osteoblasts. Ideally new drugs used for treatment of MM should target not only the myeloma cells but also the imbalance between bone resorption and bone formation. Statins have been shown to inhibit myeloma cell proliferation and induce apoptosis in vitro. Furthermore statins have been shown to stimulate osteoblasts and inhibit osteoclasts both in vitro and in animal models. Statins are normally used at doses around 20–80 mg/day, but in order to reach serum concentrations that can match the in vitro experiments MM patients were treated with 15 mg/kg/day of Simvastatin (HD-Sim) divided in two daily doses in this study. This high dose has previously been found to be safe for MM patients (Haematologica 2006, 91,542–545) Patients and methods: Six patients with advanced MM have been included in this pilot study, 4 males and 2 females with an average age of 68 years and an average duration of disease of 43 months. The patients were treated with 2 cycles of HD-Sim for seven days followed by a break of 21 days in a 4-weeks cycle. Two of the patients were treated with bisphosphonates during the study, and 4 had previously been treated with bisphosphonates. Endpoints are change in concentrations of markers of osteoclast activity (TRAP) or bone resorption (CTX, NTX, ICTP) or markers of bone formation (Osteocalcin and PINP). Cholesterol, OPG and DDK-1 were also measured. Results: Two patients completed the protocol with two cycles of HD-Sim at full dose, 2 patients were reduced to 7.5 mg/kg/day simvastatin in cycle 2 due to nausea and diarrhea and 2 patients left the protocol after 3 weeks (deaths not related to high dose simvastatin). All patients experienced gastrointestinal toxicity grade 1–2. Myalgia and other muscular symptoms grade 1–2 were reported by 5 patients but were not associated with an increase in creatin kinase. TRAP and NTX activity in serum increased for all 6 patients during the seven days of treatment with HD-Sim indicating that bone resorption may have been stimulated rather than inhibited. The other markers of bone resorption and the bone formation markers showed no change. All patients responded with a significantly reduced level of cholesterol in serum. None of the patients showed any reduction in free monoclonal light chains or monoclonal proteins in serum during treatment with HD-Sim and 2 of the 4 patients completing the protocol showed progression of diseases. Conclusion: This pilot study of HD-Sim in advanced MM has been terminated due to lack of response and evidence from two markers of osteoclast activity (TRAP) and bone resorption (NTX) that HD-Sim may be harmful rather than beneficial in MM.

Bortezomib-Thalidomide-Dexamethasone as Primary Induction Therapy for Newly Diagnosed Multiple Myeloma Significantly Decreases Bone Resorption While Sparing Bone Formation as Compared to Thalidomide-Dexamethasone

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5117-5117 ◽  
Author(s):  
Patrizia Tosi ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
Giulia Perrone ◽  
Michela Ceccolini ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Bone Resorption ◽  
Bone Formation ◽  
Induction Therapy ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Bone Formation Markers

Abstract Bone disease occurs in approximately 80% of patients with newly diagnosed multiple myeloma (MM) and is caused by the interaction of the neoplastic clone with bone marrow microenvironment, ultimately resulting in an altered balance between bone resorption and bone formation. It has been previously reported that therapies aimed at eradicating the myeloma clone could contribute to decrease bone resorption, even though bone formation remains impaired even in responding patients, due to the use of high-dose steroids. It has been recently demonstrated, both in vitro and in animal models, that Bortezomib improves bone formation by stimulating osteoblasts. In order to test whether this activity was retained also in vivo, we evaluated markers of bone resorption (serum crosslaps) and bone formation (serum osteocalcin-OC and bone alkaline phosphatase - BAP) in a series of patients who were enrolled in the “Bologna 2005” phase III clinical trial at our Center. By study design, after registration patients were randomized to receive three 21-days courses of induction therapy with either VTD (Bortezomib, 1.3 mg/sqm on d 1, 4, 8, and 11, plus Dexamethasone, 40 mg on each day of and after Bortezomib administration plus Thalidomide 200 mg/d from d 1 to 63.) or TD (Thalidomide as in VTD and Dexamethasone 40 mg/d on d 1–4 and 9–12 of every 21-d cycle), prior to stem cell collection and double autologous stem cell transplantation. As of January 2008, 27 patients (19 male and 8 female, median age = 57.5 yrs) entered the sub-study; of these, 15 and 12 patients were randomized in the VTD and TD arm, respectively. At diagnosis, both groups of patients showed a marked increase in serum crosslaps as compared to upper baseline limit (7321±1445pmol/L in the VTD arm and 11140±2576pmol/L in the TD arm) while both OC and BAP were reduced as compared to lower baseline limits. After completion of the induction therapy, serum crosslaps were significantly decreased in both treatment groups (2747±319pmol/L in VTD arm, p=0.007; 3686±1084pmol/L in the TD arm, p=0.0015). In the TD group a significant further reduction in bone formation markers was also observed (42% reduction in serum OC and 30% in BAP, p=0.03 and 0.04 as compared to pre-treatment values); on the contrary, in the VTD arm both OC and BAP were not significantly decreased as compared to baseline values (15% and 11% for OC and BAP, respectively). These data suggest that incorporation of Bortezomib into induction therapy counteracts the inhibitory effects of high-dose steroids on osteoblastogenesis, thus sparing bone formation.

Semaphorin 4D to suppress bone formation in multiple myeloma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8039-8039 ◽  
Author(s):  
Konstantinos Lontos ◽  
Juraj Adamik ◽  
Peng Zhang ◽  
Quanhong Sun ◽  
David Roodman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Cell Line ◽  
Cancer Cell Line ◽  
Myeloma Cell ◽  
Conditioned Media ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Semaphorin 4D ◽  
Pre Treatment

8039 Background: Myeloma bone disease is characterized by osteoclast activation and long-term osteoblast suppression. We investigated if Semaphorin 4D (Sema4D; CD100) plays a role in these processes. Sema4D has been shown to be a potent osteoblast inhibitor (Negishi-Koga T et al, Nat Med. 2011). A study recently identified that the breast cancer cell line MDA-MB-231 utilizes Sema4D to create osteolysis (Yang Y et al, PLOS One 2016). There have been previous data that Sema4D is increased in the serum of myeloma patients (Terpos et al, Blood 2012) and that co-culturing myeloma cell lines with osteocytes increases the expression of Sema4D mRNA in both (Suvannasankha et al, Blood 2016). We sought to investigate if myeloma cells are using Sema4D to suppress bone formation and if they affect the levels of Sema4D produced by osteoclasts. Methods: We used lentivirus carrying shRNA for Sema4D or control (Scr) to knock down the level of the protein in the 5TGM1 murine myeloma cell line. Knockdown was verified by qPCR and Western Blot. We subsequently co-cultured the 5TGM1 cells with the MC3T3-subclone M4 (MC4) murine stromal cell line for 2 days, removed the myeloma cells and then differentiated the MC4 cells using ascorbic acid and β-glycerolphosphate. At day 5, we analyzed the cells for Runx2 (a critical gene for the differentiation of stromal cells into osteoblasts) expression utilizing qPCR. Also, we performed qPCR in primary osteoclast (OCL) mouse cells differentiating into OCL with RANKL with or without pre-treatment with myeloma-conditioned media for 3 days before the addition of RANKL. Results: When 5TGM1-Scr were co-cultured with MC4 cells the expression of Runx2 on day 5 was decreased (p=0.02). Strikingly, the 5TGM1-shSema4D cells when co-cultured with MC4s did not have the same effect and allowed the upregulation of Runx2 expression on day 5 (p=0.01). Myeloma-conditioned media increased Sema4D expression by OCL throughout the 5 days of differentiation 2 to 3-fold (p=0.01 for day 5). Conclusions: The myeloma cells seem to be utilizing Sema4D both directly and indirectly to inhibit bone formation. Targeted therapy against Sema4D may improve outcomes and fracture-free survival for multiple myeloma patients.

HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma

Blood ◽  
2006 ◽  
Vol 109 (7) ◽  
pp. 3024-3030 ◽  
Author(s):  
Therese Standal ◽  
Niels Abildgaard ◽  
Unn-Merete Fagerli ◽  
Berit Stordal ◽  
Øyvind Hjertner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Alkaline Phosphatase ◽  
Bone Formation ◽  
Bone Disease ◽  
Nuclear Translocation ◽  
Osteolytic Lesion ◽  
Bmp Signaling ◽  
Myoid Cell ◽  
Osteoblast Activity

AbstractThe bone disease in multiple myeloma is caused by an uncoupling of bone formation from bone resorption. A key difference between patients with and patients without osteolytic lesion is that the latter have fewer and less active osteoblasts. Hepatocyte growth factor (HGF) is often produced by myeloma cells and is found at high concentrations in the bone marrow of patients with multiple myeloma. Here we show that HGF inhibited bone morphogenetic protein (BMP)–induced in vitro osteoblastogenesis. Thus, HGF inhibited BMP-induced expression of alkaline phosphatase in human mesenchymal stem cells (hMSCs) and the murine myoid cell line C2C12, as well as mineralization by hMSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF promoted proliferation of hMSCs, and the BMP-induced halt in proliferation was overridden by HGF, keeping the cells in a proliferative, undifferentiating state. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation of how HGF inhibits BMP signaling. The in vitro data were supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase (rho = −0.45, P = .008), in sera from 34 patients with myeloma. These observations suggest that HGF inhibits bone formation in multiple myeloma.

Bone Remodeling in Patients with Relapsed/Refractory Multiple Myeloma Who Receive Lenalidomide-Based Regimens.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4745-4745
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Efstathios Kastritis ◽  
Eirini Katodritou ◽  
Xenophon Papanikolaou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Bone Remodeling ◽  
Response To Therapy ◽  
Type I ◽  
Fracture Group ◽  
Lytic Lesions ◽  
Tracp 5B

Abstract Lenalidomide in combination with dexamethasone is very effective for the management of refractory/relapsed multiple myeloma (MM). However, there is very little information for the effect of lenalidomide on bone metabolism in MM. We evaluated bone remodeling in 36 patients (22M/14F; median age 64 years) with refractory/relapsed MM who received lenalidomide-based regimens: 27 received the combination of lenalidomide at the standard dose of 25mg/day x 21 days, every 28 days, with either high (n=18) or low (n=9) dose dexamethasone, while 9 patients received the combination of lenalidomide/low dose dexamethasone plus bortezomib (BDR) at a dose of 1 mg/m2, iv, on days 1, 4, 8, 11 every 28 days. The following serum indices of bone turnover were measured on day 1 of cycle 1, and then on day 28 of cycle 3: 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 20 healthy controls of similar gender and age. The median number of previous therapies was 3 (range: 2–7). At baseline, 9 patients had no lytic lesions (group A), while 3 patients had 1–3 lytic lesions (group B) and 24 patients had more than 3 lytic lesions and/or a pathological fracture (group C) in plain radiography of the skeleton. After 3 cycles of therapy the objective response (CR+PR) rate was 77% (21/27) in lenalidomide/dexamethasone patients and 55% (5/9) in BDR patients. MM patients at baseline had increased levels of Dkk-1 (p=0.002), sRANKL (p=0.04), and both markers of bone resorption (p<0.01) compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.01). Patients with advanced bone disease (group C) had increased levels of CTX (p<0.001), TRACP-5b (p<0.01), Dkk-1 (p=0.04) and reduced levels of OC (p=0.04) compared with all others. Moreover, serum levels of DKK-1 correlated with TRACP-5b (r=0.614, p<0.0001), CTX (r=0.29, p=0.03), sRANKL (r=0.423, p=0.001) and OPG (r=0.572, p<0.0001). The administration of lenalidomide-based regimens produced only a reduction of Dkk-1 (p=0.04) and TRACP-5b (p=0.03) after 3 cycles of therapy. Interestingly, patients who received BDR showed a dramatic reduction of sRANKL (p=0.02), sRANKL/OPG ratio (p=0.03) and Dkk-1 (p=0.02), which associated with an increase in both markers of bone formation (p=0.04). The % reduction of sRANKL and TRACP-5b and the % increase of bALP and OC was higher in BDR patients compared with others. There was no correlation between response to therapy and bone markers’ changes. In conclusion, the combination of lenalidomide plus dexamethasone seems not to have a clear effect on bone metabolism after 3 cycles of therapy, possibly due to administration of high dose dexamethasone in the majority of patients. BDR patients had a beneficial effect mainly on bone formation, reflecting the bone anabolic effect of bortezomib and/or the lower dose of dexamethasone given in these patients. Longer follow-up is needed to exact final conclusions for the effect of lenalidomide on bone metabolism in relapsed/refractory MM.

High Serum Sclerostin Correlates with Advanced Stage, Increased Bone Resorption, Reduced Osteoblast Function, and Poor Survival in Newly-Diagnosed Patients with Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 425-425 ◽  
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Eirini Katodritou ◽  
Cornelia Bratengeier ◽  
Brigitte Lindner ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Detection Limit ◽  
Bone Resorption ◽  
Bone Formation ◽  
Median Survival ◽  
Healthy Controls ◽  
Poor Survival ◽  
Myeloma Cells ◽  
Osteoblast Function ◽  
Standard Range

Abstract Abstract 425 Multiple myeloma (MM) is characterized by the presence of lytic bone disease due to increased osteoclast activity which is accompanied by reduced osteoblast function. To-date dickkopf-1 (Dkk-1) is considered as the main osteoblast inhibitor which is overproduced by myeloma cells and inhibits Wnt signaling leading to osteoblast exhaustion. Sclerostin is another canonical Wnt antagonist through its binding to low-density lipoprotein-receptor-related protein 5/6. Sclerostin is specifically expressed by osteocytes and inhibits bone morphogenic protein-induced osteoblast differentiation and ectopic bone formation. Osteonectin (SPARC) is a multi-faceted protein that belongs to a family of matricellular proteins. It is secreted by osteoblasts during bone formation, initiating mineralization and promoting mineral crystal formation. SPARC shows affinity for collagen in addition to bone mineral calcium. The aim of this study contacted by the Greek Myeloma Study Group in collaboration with Biomarker Design Forschungs GmbH (BDF), Vienna, Austria was to evaluate, for the first time in the literature, the serum levels of sclerostin in patients with MM and explore possible correlations with clinical and laboratory data, including SPARC levels, ISS stage and survival. One hundred and fifty-seven patients (87M/70F, median age 68 years) with MM at diagnosis before the administration of any type of therapy, including bisphosphonates, were evaluated. Serum sclerostin and SPARC were measured using an ELISA methodology developed by BDF for Biomedica Medizinprodukte GmbH & Co KG (Vienna, Austria). Both assays are sandwich type ELISA using biotinylated antibodies/HRP-streptavidine for the detection of sclerostin and SPARC in the serum. The detection limit of the sclerostin ELISA was 0.18 ng/ml and the coefficient of variation (CV) 6%. The standard range was set from 0.3-3 ng/ml. For the SPARC ELISA we found a detection limit of 1.95 ng/ml and CVs of 8% using a standard range from 5-130 ng/ml. Serum sclerostin and SPARC were determined in MM patients, 21 patients with MGUS and 21 healthy controls, of similar gender and age. Bone remodeling was also studied by the measurement of a series of serum indices within one week from diagnosis: i) osteoclast regulators [sRANKL and osteoprotegerin (OPG)], ii) Dkk-1, iii) bone resorption markers [C-terminal cross-linking telopeptide of collagen type-I (CTX) and 5b-isoenzyme of tartrate resistant acid phosphatase (TRACP-5b)], and iv) bone formation markers [bone-specific alkaline phosphatase (bALP) and osteocalcin (OC)]. Patients with MM had increased levels of serum sclerostin compared with MGUS patients (mean value±SD: 0.48±0.46 vs. 0.26±0.29 ng/ml; p=0.004) and healthy controls (0.31±0.20 ng/ml, p=0.01). In contrast, both patients with MM and MGUS had reduced levels of serum SPARC (26.3±16.2 and 27.2±18.0 ng/ml, respectively) compared to controls (52.8±50.2 ng/ml; p<0.001). Sclerostin values strongly correlated with beta2-microglobulin (r=0.354, p<0.0001), cystatin-C (r=0.389, p<0.0001), serum creatinine (r=0.380, p<0.0001), and bALP (r=-0.541, p<0.0001). No correlations were observed between sclerostin with sRANKL, OPG, Dkk-1 or SPARC. Patients with advanced bone disease assessed by conventional radiography (>3 lytic lesions and/or a pathological fracture) had a borderline increase of sclerostin compared to all others (median value: 0.51 vs. 0.41 ng/ml, p=0.09). Patients with ISS-3 disease had increased levels of sclerostin compared to patients with ISS-1 and ISS-2 MM (ANOVA p=0.001). Median survival of MM patients was 48 months and median follow-up period was 20 months. Patients who had a serum sclerostin of ≥0.62 ng/ml (upper quartile, n=40 patients) had a median survival of 27 months, while median survival of all other patients was 98 months (p=0.031). In conclusion, our study provided evidence that sclerostin is increased in the serum of patients with MM and correlates with advanced ISS stage, increased bone resorption, reduced osteoblast function and poor survival. SPARC is reduced in MM possibly confirming the reduced osteoblast function observed in these patients. Sclerostin seems to participate in the biology of MM and thus it may be a possible target for the development of novel therapies that can both increase osteoblast function and target myeloma cells. Disclosures: No relevant conflicts of interest to declare.

Myeloma Cells Induce Osteoblast Suppression through Sclerostin Secretion

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2961-2961 ◽  
Author(s):  
Silvia Colucci ◽  
Giacomina Brunetti ◽  
Angela Oranger ◽  
Giorgio Mori ◽  
Francesca Sardone ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Formation ◽  
Bone Disease ◽  
Culture System ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
Type I ◽  
Myeloma Cells ◽  
Myeloma Bone Disease ◽  
Osteoblast Activity

Abstract Abstract 2961 Reduced osteoblast activity contributes to the development of multiple myeloma-bone disease. Wingless-type (Wnt) signalling pathway is critical in osteoblastogenesis, and it is negatively regulated by molecules such as frizzled-related proteins (sFRPs), Dickkopf proteins (DKKs) and sclerostin. Myeloma cells are known to induce inhibition of osteoblastogenesis through Wnt antagonists such as DKK-1 and sFRP-2 and -3 whereas the role of sclerostin, an osteocyte-expressed negative regulator of bone formation, has not been yet investigated. We provide novel evidence showing sclerostin expression by myeloma cells from patients with multiple myeloma-bone disease and human myeloma cell lines (HMCLs). By means of a co-culture system of bone marrow stromal cells (BMSCs) and HMCLs, we demonstrated that sclerostin expression by myeloma cells and HMCLs is responsible for reduced expression of major osteoblastic specific proteins namely bone-specific alkaline phosphatase, collagen-type I, bone sialoprotein II and osteocalcin as well as decreased mineralized nodule formation and attenuated expression of member of the AP-1 transcription factor family (i.e. Fra-1, Fra-2 and Jun-D). The addition of a neutralizing anti-sclerostin antibody to our co-culture system can restore the above parameters, through the intranuclear accumulation of β-catenin in BMSCs. On the other hand, we demonstrated that sclerostin is also involved in inducing increased receptor activator of nuclear factor-k B ligand (RANKL) and decreased osteoprotegerin (OPG) expression in osteoblasts, contributing to the enhanced osteoclast activity occurring in patients with multiple myeloma-bone disease. Our data suggest that myeloma cells contribute to the suppression of bone formation through sclerostin secretion. Disclosures: No relevant conflicts of interest to declare.

Disregulated Osteogenesis By Mesenchymal Stromal Cells (MSC) After In Vivo Exposure To Multiple Myeloma: Studies In a Novel Humanized Mouse Model For Bone Remodelling In Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1906-1906
Author(s):  
Richard W.J. Groen ◽  
Willy A. Noort ◽  
Jessica Sigmans ◽  
Aniek van Stralen ◽  
Linda Aalders ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Mouse Model ◽  
Bone Formation ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Humanized Mouse ◽  
Humanized Mouse Model ◽  
Hybrid Scaffolds

Abstract Multiple myeloma (MM), a B-cell neoplasm characterized by a clonal expansion of malignant plasma cells in the bone marrow (BM), is accompanied by osteolytic lesions and/or diffuse osteopenia in up to 90% of the patients. Even after successful treatment, these MM-induced bone lesions do not normalize. We hypothesized that this might be caused by MM-induced irreversible impairment of the osteoblast function in the BM microenvironment. To study this bone remodeling processes in MM we used a recently developed, humanized mouse model of MM that allows engraftment and outgrowth of patient MM (pMM) cells in a humanized BM niche. To this end, ceramic scaffolds are seeded with culture-expanded human mesenchymal stromal cells (MSCs) from human BM, differentiated in vitro to osteoblasts for 1 week, then implanted subcutaneously in immune-deficient RAG2-/-gc-/--mice and after 6-8 weeks a layer of human bone is deposited on the surface of the scaffolds. Following the injection of luciferase-GFP gene marked primary MM cells (pMM), this results in homing and outgrowth of pMM in the scaffolds (Groen et al., Blood 2012). Here we describe a modification of this in vivo model, by co-implanting MSC loaded scaffolds, with pMM cells adhered to the hybrid scaffolds, at one side of the mouse, and with hybrid scaffolds only (without pMM) at the other side of the mouse. At this contra-lateral location bone formation can take place undisturbed (i.e., not affected by the presence of MM) and serves as an internal control for the osteogenic potential of the osteoblasts. Thus this model allows us to study bidirectional interactions between pMM cells and the osteoblast and the resulting inhibition of osteogenesis. Here we report that outgrowth pMM cells indeed resulted in on average 50-75% decrease in bone formation, and, using bioluminescence imaging, we found an inverse correlation between the size of the tumor and the amount of bone formation: with increasing tumor size, the amount of bone formed was less. Human AML growing in the scaffolds (serving as control) does not influence the bone forming process. At the end of the experiment when we analyzed gene expression in the human stromal cells (CD73+ CD90+ CD105+) that we cultured from scaffolds containing pMM tumors, we found a significant reduction in expression of transcripts for alkaline phosphatase (ALP), collagen1A1 (colA1), osteoglycin (OGN), osteomodulin (OMD), and abnormal spindle-like microcephaly associated (ASPM), genes that have been implicated in osteogenesis. These data suggest that pMM cells interfere with the osteogenic differentiation of MSCs in the context of an in vivo biocompatible scaffold engineered to simulate the human BM microenvironment. Taken together, our data show that co-implanting MSCs together with the pMM cells can serve as a model to study the effect of pMM cells on osteogenesis, which provides a tool to unravel the mutual interaction between MM cells and the bone marrow microenvironment. Disclosures: No relevant conflicts of interest to declare.

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