Improving bone health via modulation of glycosphingolipid metabolism and autophagy

Abstract Patients with multiple myeloma (MM), an incurable malignancy of plasma cells, frequently develop osteolytic bone lesions. In this study, glycosphingolipids were essential in promoting autophagic degradation of the signaling molecule TRAF3, a key step in bone-resorbing osteoclast differentiation. Specifically altering the glycosphingolipid composition with eliglustat, an FDA approved glucosylceramide synthase inhibitor, arrested osteoclast differentiation; this could be rescued by exogenous addition of the missing glycosphingolipids. Eliglustat significantly reduced bone disease in several preclinical models of MM by inhibiting osteoclastogenesis and, due to its unique mode of action, it was able to act in combination with existing bone protective drugs. Furthermore, eliglustat arrested osteoclast differentiation from the bone marrow of MM patients in a glycosphingolipid-dependent way. This work identifies both the mechanism by which glucosylceramide synthase inhibition blocks autophagic degradation of TRAF3 to reduce osteoclastogenesis as well as highlighting the translational potential of eliglustat to be combined with current treatments.

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Preclinical models of human multiple myeloma subgroups

10.1101/2021.08.28.458010 ◽

2021 ◽

Author(s):

Wiebke Winkler ◽

Carlota Farré Díaz ◽

Eric Blanc ◽

Hanna Napieczynska ◽

Patrick Langner ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Germinal Center ◽

Plasma Cells ◽

Bone Lesions ◽

Preclinical Models ◽

Co Activation ◽

Human Multiple Myeloma ◽

First Time

Multiple myeloma (MM), a tumor of germinal center (GC)-experienced plasma cells, comprises distinct genetic subgroups, such as the t(11;14)/CCND1 and the t(4;14)/MMSET subtype. We have generated subgroup-specific MM models by the GC B cell-specific co-activation of Ccnd1 or MMSET with a constitutively active Ikk2 mutant, mimicking the secondary NFκB activation frequently seen in human MM. Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed a pronounced, clonally restricted plasma cell outgrowth with age, accompanied by serum M spikes, bone marrow insufficiency and bone lesions. The transgenic plasma cells could be propagated in vivo and showed transcriptional profiles resembling their human counterparts. Thus, we show that Ccnd1 and MMSET cooperate with NFκB in MM pathogenesis, considering for the first time the genetic heterogeneity of MM for the generation of preclinical models.

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A novel glucosylceramide synthase inhibitor attenuates alpha synuclein pathology and lysosomal dysfunction in preclinical models of synucleinopathy

Neurobiology of Disease ◽

10.1016/j.nbd.2021.105507 ◽

2021 ◽

pp. 105507

Author(s):

Mali Cosden ◽

Sarah Jinn ◽

Lihang Yao ◽

Cheryl A. Gretzula ◽

Monika Kandebo ◽

...

Keyword(s):

Alpha Synuclein ◽

Preclinical Models ◽

Glucosylceramide Synthase ◽

Lysosomal Dysfunction ◽

Synthase Inhibitor

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Bone disease as the first manifestation of systemic AL-amyloidosis

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.07.000775 ◽

2020 ◽

Vol 92 (7) ◽

pp. 85-89

Author(s):

L. P. Mendeleeva ◽

I. G. Rekhtina ◽

A. M. Kovrigina ◽

I. E. Kostina ◽

V. A. Khyshova ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bone Disease ◽

Plasma Cells ◽

Interventricular Septum ◽

Bone Destruction ◽

Amyloid Deposition ◽

Bone Lesions ◽

Al Amyloidosis ◽

Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

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Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases

Bone Research ◽

10.1038/s41413-021-00136-2 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Navatha Shree Polavaram ◽

Samikshan Dutta ◽

Ridwan Islam ◽

Arup K. Bag ◽

Sohini Roy ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Cells ◽

Molecular Mechanisms ◽

Osteoclast Differentiation ◽

Potential Effect ◽

Tumor Burden ◽

Bone Lesions ◽

Prostate Cancer Cells

AbstractUnderstanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target. Since, osteoclasts present in the tumor microenvironment express NRP2, we have investigated the potential effect of targeting NRP2 in osteoclasts. Our results revealed NRP2 negatively regulates osteoclast differentiation and function in the presence of prostate cancer cells that promotes mixed bone lesions. Our study further delineated the molecular mechanisms by which NRP2 regulates osteoclast function. Interestingly, depletion of NRP2 in osteoclasts in vivo showed a decrease in the overall prostate tumor burden in the bone. These results therefore indicate that targeting NRP2 in prostate cancer cells as well as in the osteoclastic compartment can be beneficial in the treatment of prostate cancer bone metastasis.

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An Unprecedented Case of p190 BCR-ABL Chronic Myeloid Leukemia Diagnosed during Treatment for Multiple Myeloma: A Case Report and Review of the Literature

Case Reports in Hematology ◽

10.1155/2018/7863943 ◽

2018 ◽

Vol 2018 ◽

pp. 1-5

Author(s):

Kosuke Miki ◽

Naoshi Obara ◽

Kenichi Makishima ◽

Tatsuhiro Sakamoto ◽

Manabu Kusakabe ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Plasma Cells ◽

Bone Marrow Examination ◽

Bone Lesions ◽

Dexamethasone Treatment ◽

Lytic Bone Lesions

We report the case of a 76-year-old man who was diagnosed as having chronic myeloid leukemia (CML) with p190 BCR-ABL while receiving treatment for symptomatic multiple myeloma (MM). The diagnosis of MM was based on the presence of serum M-protein, abnormal plasma cells in the bone marrow, and lytic bone lesions. The patient achieved a partial response to lenalidomide and dexamethasone treatment. However, 2 years after the diagnosis of MM, the patient developed leukocytosis with granulocytosis, anemia, and thrombocytopenia. Bone marrow examination revealed Philadelphia chromosomes and chimeric p190 BCR-ABL mRNA. Fluorescence in situ hybridization also revealed BCR-ABL-positive neutrophils in the peripheral blood, which suggested the emergence of CML with p190 BCR-ABL. The codevelopment of MM and CML is very rare, and this is the first report describing p190 BCR-ABL-type CML coexisting with MM. Moreover, we have reviewed the literature regarding the coexistence of these diseases.

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The Evolution in The Treatment of Multiple Myeloma Towards Targeted Magnetic Molecularly Imprinted Nanomedicines

Edelweiss: Cancer Open Access ◽

10.33805/2689-6737.101 ◽

2015 ◽

pp. 1-2

Author(s):

Edgar Pérez-Herrero

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Bacterial Infections ◽

Plasma Cells ◽

The Body ◽

Western World ◽

Bone Lesions ◽

Non Hodgkin Lymphoma ◽

Clonal Proliferation ◽

Tract Infections

Multiple myeloma is the second more frequently haematological cancer in the western world, after non-Hodgkin lymphoma, being about the 1-2 % of all the cancers cases and the 10-13% of hematologic diseases. The disease is caused by an uncontrolled clonal proliferation of plasma cells in the bone marrow that accumulate in different parts of the body, usually in the bone marrow, around some bones, and rarely in other tissues, forming tumor deposits, called plasmocytomas. This uncontrolled clonal proliferation of plasma cells produces the secretion of an abnormal monoclonal immunoglobulin (paraprotein or M-protein) and prevents the formation of the other antibodies produced by the normal plasma cells that are destroyed. The anormal secretion of paraproteins unbalance the osteoblastosis and osteoclastosis processes, leading to bone lesions that cause lytic bone deposits and the release of calcium from bones (hypercalcemia) that may produce renal failure. Regions affected by bone lesions are the skull, spine, ribs, sternum, pelvis and bones that form part of the shoulders and hips. The substitution of the healthy bone marrow by infiltrating malignant cells and the inhibition of the normal production of red blood cells produce anaemia, thrombocytopenia and leukopenia. Multiple myeloma patients are immunosuppressed because of leukopenia and the abnormal immunoglobulin production caused by the uncontrolled clonal proliferation of plasma cells, being susceptible to bacterial infections, like pneumonias and urinary tract infections. The interaction of immunoglobulin with hemostatic mechanisms may lead to haemorrhagic diathesis or thrombosis. Also, disorders of the central and peripheral nervous system are part of the disease, being the more common neurological manifestations the spinal cord compressions and the peripheral neuropathies.

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Production of interleukin-1 by bone marrow myeloma cells

Blood ◽

10.1182/blood.v74.1.380.bloodjournal741380 ◽

1989 ◽

Vol 74 (1) ◽

pp. 380-387 ◽

Cited By ~ 1

Author(s):

F Cozzolino ◽

M Torcia ◽

D Aldinucci ◽

A Rubartelli ◽

A Miliani ◽

...

Keyword(s):

Bone Marrow ◽

Plasma Cell ◽

Plasma Cells ◽

Interleukin 1 ◽

Long Bone ◽

Bone Lesions ◽

Normal Donor ◽

Biologic Activity ◽

Culture Supernatants

Plasma cells isolated from bone marrow (BM) aspirates of 12 patients with multiple myeloma (MM) and nine patients with monoclonal gammopathy of undetermined significance (MGUS) were analyzed for production of cytokines with bone-resorbing activity, such as interleukin-1 (IL-1), tumor necrosis factor (TNF), and lymphotoxin (LT). Culture supernatants of plasma cells from MM, but not from MGUS or normal donor, invariably contained high amounts of IL-1-beta and lower amounts of IL-1-alpha. With a single exception, TNF/LT biologic activity was not detected in the same supernatants. IL-6 was present in two of five supernatants tested. Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell. Unexpectedly, the mRNA extracted from MM plasma cell hybridized with TNF- and LT- specific, as well as IL-1-specific probes, although the culture supernatants did not contain detectable TNF/LT biologic activity. When tested in the fetal rat long bone assay, MM plasma cell supernatants displayed a strong osteoclast-activating factor (OAF) activity, which was greatly reduced but not completely abolished by neutralizing anti- IL-1 antibodies. Anti-TNF or anti-LT antibodies were ineffective in the same test. We conclude that the IL-1 released in vivo by malignant plasma cells has a major role in pathogenesis of lytic bone lesions of human MM.

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Is a severe and early neuropathy related to bortezomib? Is it related to the treatment response?

Hematology & Transfusion International Journal ◽

10.15406/htij.2020.08.00216 ◽

2020 ◽

Vol 8 (2) ◽

pp. 19-21

Author(s):

Maria Pereiro Sanchez ◽

María Perfecta Fernández Gonzalez ◽

María del Carmen López Doldán ◽

Aurea María Gómez Marquez ◽

José Luis Sastre Moral ◽

...

Keyword(s):

Stem Cell ◽

Standard Treatment ◽

Stem Cell Transplant ◽

Plasma Cells ◽

White Male ◽

Complete Response ◽

Autologous Stem Cell Transplant ◽

Lower Limbs ◽

Bone Lesions ◽

Cell Transplant

Myeloma is characterized by the neoplastic proliferation of a clone of plasma cells that invades the bone, causes destruction of the skeleton, and causes bone pain and fractures. In addition, other important features are anemia, hypercalcemia and renal failure. The standard treatment in Spain for autologous stem cell transplant (ASCT)-eligible patients is VTD (bortezomib, thalidomide, dexamethasone). Both bortezomib and thalidomide can cause or exacerbate an existing neuropathy. The mechanism by which they produce it is different in the two drugs.1 A 52-year-old white male was referred to our hospital for the evaluation of anemia (12 g/dL) and serum monoclonal protein (>4 g/dL). The diagnosis was a high cytogenetic risk MM stage R-ISS IIIA, without bone lesions. He only presented mild anemia. He started treatment with standard doses and in accordance to the usual protocol in a candidate patient for autologous stem cell transplant, based on a thalidomide and bortezomib scheme. On the 15th day of the 2nd cycle, the patient showed an autonomic neuropathy and an affectation of the deep sensibility, predominantly the vibratory and proprioceptive with generalized muscle weakness predominant in the lower limbs. He had no pain. He was totally dependent for the basic activities of daily life. Regarding the MM response, the patient showed a strict complete response. This case illustrates a young man with a high cytogenetic risk MM who developed an acute and early polyneuropathy grade IV after 1.5 cycles of standard treatment and with myeloma in strict complete response. The remarkable aspect about this case is the severe and early neuropathy, and an early, deep and persistent myeloma response. On some occasions this relationship has been reported, and we report an example of it.

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