Megakaryocyte-driven changes in bone health: lessons from mouse models of myelofibrosis and related disorders

2021 ◽  
Author(s):  
Mariya Stavnichuk ◽  
Svetlana V. Komarova
Keyword(s):  
Bone Marrow ◽  
Mouse Models ◽  
Cell Function ◽  
Bone Cells ◽  
Bone Marrow Cells ◽  
Bone Cell ◽  
Bone Architecture ◽  
Bone Homeostasis

Over the years, numerous studies demonstrated reciprocal communications between processes of bone marrow hematopoiesis and bone remodeling. Megakaryocytes, rare bone marrow cells responsible for platelet production, were demonstrated to be involved in bone homeostasis. Myelofibrosis, characterized by an increase in pleomorphic megakaryocytes in the bone marrow, commonly leads to the development of osteosclerosis. In vivo, an increase in megakaryocyte number was shown to result in osteosclerosis in GATA-1low, NF-E2-/-, TPOhigh, Mpllf/f;PF4cre, Lnk-/-, Mpig6b-/-, Mpig6bfl/fl;Gp1ba-Cr+/KI, Pt-vWD mouse models. In vitro, megakaryocytes stimulate osteoblast proliferation and have variable effects on osteoclast proliferation and activity through soluble factors and direct cell-cell communications. Intriguingly, new studies revealed that the ability of megakaryocytes to communicate with bone cells is affected by the age and sex of animals. This mini-review summarises changes seen in bone architecture and bone cell function in mouse models with an elevated number of megakaryocytes and the effects megakaryocytes have on osteoblasts and osteoclasts in vitro, and discusses potential molecular players that can mediate these effects.

scholarly journals Protocol of Co-Culture of Human Osteoblasts and Osteoclasts to Test Biomaterials for Bone Tissue Engineering

2022 ◽  
Vol 5 (1) ◽  
pp. 8
Author(s):  
Giorgia Borciani ◽  
Giorgia Montalbano ◽  
Nicola Baldini ◽  
Chiara Vitale-Brovarone ◽  
Gabriela Ciapetti
Keyword(s):  
Tissue Engineering ◽  
Bone Tissue Engineering ◽  
Bone Tissue ◽  
Bone Cells ◽  
Bone Cell ◽  
Seeding Density ◽  
Bone Homeostasis ◽  
Bone Microenvironment

New biomaterials and scaffolds for bone tissue engineering (BTE) applications require to be tested in a bone microenvironment reliable model. On this assumption, the in vitro laboratory protocols with bone cells represent worthy experimental systems improving our knowledge about bone homeostasis, reducing the costs of experimentation. To this day, several models of the bone microenvironment are reported in the literature, but few delineate a protocol for testing new biomaterials using bone cells. Herein we propose a clear protocol to set up an indirect co-culture system of human-derived osteoblasts and osteoclast precursors, providing well-defined criteria such as the cell seeding density, cell:cell ratio, the culture medium, and the proofs of differentiation. The material to be tested may be easily introduced in the system and the cell response analyzed. The physical separation of osteoblasts and osteoclasts allows distinguishing the effects of the material onto the two cell types and to evaluate the correlation between material and cell behavior, cell morphology, and adhesion. The whole protocol requires about 4 to 6 weeks with an intermediate level of expertise. The system is an in vitro model of the bone remodeling system useful in testing innovative materials for bone regeneration, and potentially exploitable in different application fields. The use of human primary cells represents a close replica of the bone cell cooperation in vivo and may be employed as a feasible system to test materials and scaffolds for bone substitution and regeneration.

scholarly journals HIF-1α is a negative regulator of plasmacytoid DC development in vitro and in vivo

Blood ◽  
2012 ◽  
Vol 120 (15) ◽  
pp. 3001-3006 ◽  
Author(s):  
Andreas Weigert ◽  
Benjamin Weichand ◽  
Divya Sekar ◽  
Weixiao Sha ◽  
Christina Hahn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Function ◽  
Bone Marrow Cells ◽  
Negative Regulator ◽  
Low Oxygen ◽  
Hematopoietic Stem ◽  
Lineage Differentiation ◽  
Marrow Cells

Abstract Hypoxia-inducible factors (HIFs) regulate hematopoiesis in the embryo and maintain hematopoietic stem cell function in the adult. How hypoxia and HIFs contribute to hematopoietic lineage differentiation in the adult is ill defined. Here we provide evidence that HIF-1 limits differentiation of precursors into plasmacytoid dendritic cells (pDCs). Low oxygen up-regulated inhibitor of DNA binding 2 (ID2) and suppressed Flt3-L–induced differentiation of bone marrow cells to pDCs in wild-type but not HIF-1αfl/fl LysM-Cre bone marrow cells. Moreover, pDC differentiated normally in hypoxic ID2−/− bone marrow cultures. Finally, we observed elevated pDC frequencies in bone marrow, blood, and spleen of HIF-1αfl/fl LysM-Cre and ID2−/−, but not HIF-2αfl/fl LysM-Cre mice. Our data indicate that the low oxygen content in the bone marrow might limit pDC development. This might be an environmental mechanism to restrict the numbers of these potentially autoreactive cells.

scholarly journals Syndecan-1 Is a Multifunctional Regulator of Myeloma Pathobiology: Control of Tumor Cell Survival, Growth, and Bone Cell Differentiation

Blood ◽  
1998 ◽  
Vol 91 (8) ◽  
pp. 2679-2688 ◽  
Author(s):  
Madhav V. Dhodapkar ◽  
Etsuko Abe ◽  
Allison Theus ◽  
Marie Lacy ◽  
J. Kevin Langford ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Heparan Sulfate ◽  
Bone Disease ◽  
Bone Cells ◽  
Bone Marrow Cells ◽  
Myeloma Cells ◽  
Bone Cell Differentiation ◽  
Dose Dependent

Multiple myeloma is characterized by an accumulation of malignant plasma cells in the bone marrow coupled with an altered balance of osteoclasts and osteoblasts, leading to lytic bone disease. Although some of the cytokines driving this process have been characterized, little is known about the negative regulators. We show that syndecan-1 (CD 138), a heparan sulfate proteoglycan, expressed on and actively shed from the surface of most myeloma cells, induces apoptosis and inhibits the growth of myeloma tumor cells and also mediates decreased osteoclast and increased osteoblast differentiation. The addition of intact purified syndecan-1 ectodomain (1 to 6 nmol/L) to myeloma cell lines in culture leads to induction of apoptosis and dose-dependent growth inhibition, with concurrent downregulation of cyclin D1. The addition of purified syndecan-1 in picomolar concentrations to bone marrow cells in culture leads to a dose-dependent decrease in osteoclastogenesis and a smaller increase in osteoblastogenesis. In contrast to the effect on myeloma cells, the effect of syndecan-1 on osteoclastogenesis only requires the syndecan-1 heparan sulfate chains and not the intact ectodomain, suggesting that syndecan's effect on myeloma and bone cells occurs through different mechanisms. When injected in severe combined immune deficient (scid) mice, control-transfected myeloma cells (ARH-77 cells) expressing little syndecan-1 readily form tumors, leading to hind limb paralysis and lytic bone disease. However, after the injection of syndecan-1–transfected ARH-77 cells, the development of disease-related morbidity and lytic bone disease is significantly inhibited. Taken together, our data demonstrate, both in vitro and in vivo, that syndecan-1 has a significant beneficial effect on the behavior of both myeloma and bone cells and therefore may represent one of the central molecules in the regulation of myeloma pathobiology.

scholarly journals Review on material parameters to enhance bone cell function in vitro and in vivo

2020 ◽  
Vol 48 (5) ◽  
pp. 2039-2050
Author(s):  
Eric Madsen ◽  
Merjem Mededovic ◽  
David H. Kohn
Keyword(s):  
Cell Function ◽  
Bone Cells ◽  
Bone Cell ◽  
Bone Augmentation ◽  
Material Parameters ◽  
Specific Material ◽  
Resorbable Implants ◽  
Resorbable Materials

Bone plays critical roles in support, protection, movement, and metabolism. Although bone has an innate capacity for regeneration, this capacity is limited, and many bone injuries and diseases require intervention. Biomaterials are a critical component of many treatments to restore bone function and include non-resorbable implants to augment bone and resorbable materials to guide regeneration. Biomaterials can vary considerably in their biocompatibility and bioactivity, which are functions of specific material parameters. The success of biomaterials in bone augmentation and regeneration is based on their effects on the function of bone cells. Such functions include adhesion, migration, inflammation, proliferation, communication, differentiation, resorption, and vascularization. This review will focus on how different material parameters can enhance bone cell function both in vitro and in vivo.

From Mouse to Man: Redefining the Role of Insulin-Like Growth Factor-I in the Acquisition of Bone Mass

2003 ◽  
Vol 228 (3) ◽  
pp. 245-252 ◽  
Author(s):  
Shoshana Yakar ◽  
Clifford J. Rosen
Keyword(s):  
Growth Factor ◽  
Cell Function ◽  
Bone Cells ◽  
Bone Cell ◽  
Insulin Like Growth Factor ◽  
In Vivo Models ◽  
Igf I

The insulin-like growth factor system (IGF) has been linked to the process of bone acquisition through epidemiologic analyses of large cohorts and in vitro studies of bone cells. But the exact relationship between expression of IGF-I in bone and skeletal homeostasis or pathologic conditions, such as osteoporosis, remains poorly defined. Recent advances in genomic engineering have resulted in the development of better in vivo models to test the role of IGF-I during development and maintenance of the adult skeleton. It is now established that skeletal expression of IGF-I is critical for differentiative bone cell function. It may also be essential for the full anabolic effects of parathyroid hormone on trabecular bone and for some component of biomineralization. Evidence from conditional mutagenesis studies suggests that serum IGF-I may represent more than a storage depot or permissive factor during the final phase of skeletal acquisition. This work re-examines the original tenets of the “somatomedin hypothesis” in light of these newer mouse models and their remarkable skeletal phenotypes. The implications are far reaching and suggest that newer approaches for manipulating the IGF regulatory system may one day be useful as therapeutic adjuncts for the treatment of osteoporosis.

scholarly journals THE EFFECT OF HETEROLOGOUS ANTI-LYMPHOCYTE SERUM ON MOUSE HEMOPOIETIC STEM CELLS

1968 ◽  
Vol 127 (4) ◽  
pp. 731-748 ◽  
Author(s):  
Tom R. DeMeester ◽  
Norman D. Anderson ◽  
Charles F. Shaffer
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Cell Function ◽  
Bone Marrow Cells ◽  
Hemopoietic Stem Cell ◽  
Hemopoietic Stem Cells ◽  
Marrow Cells

The present study has demonstrated that rabbit anti-mouse lymphocyte serum (RAMLS) has the capability of destroying bone marrow cells and suppressing hemopoietic stem cell function. The in vitro incubation of bone marrow suspensions with RAMLS caused extensive cell lysis with an apparent preferential destruction of lymphoid, erythroid, and blastoid elements. Using the spleen colony assay, the number of functional hemopoietic stem cells was found to be markedly reduced in bone marrow populations exposed to RAMLS in vitro. Further, this loss of stem cell function could be produced by exposing marrow suspensions to small concentrations of antiserum which did not produce detectable cytotoxic effects on the general marrow population. A similar effect of RAMLS upon hemopoietic stem cells was found in vivo. The intravenous injection of RAMLS into lethally irradiated mice immediately after the infusion of isogeneic marrow cells reduced the number of spleen colonies formed, indicating that the antiserum could exhibit a deleterious effect upon stem cells in the bloodstream of the intact animal. Normal animals treated with daily subcutaneous injections of RAMLS for 3 wk had a significantly reduced marrow content of functional hemopoietic stem cells, suggesting that RAMLS can affect stem cells located in situ in the bone marrow. The experiments indicate that RAMLS possesses potential marrow toxicity.

Thrombopoietin-Induced Stimulation of Megakaryocyte- Enriched Bone Marrow Cultures

1979 ◽  
Author(s):  
K. L. Kellar ◽  
B. L. Evatt ◽  
C. R. McGrath ◽  
R. B. Ramsey
Keyword(s):  
Bone Marrow ◽  
Dna Synthesis ◽  
Bone Marrow Cells ◽  
Rabbit Plasma ◽  
Bone Marrow Cultures ◽  
Plasma Fractions ◽  
Marrow Cultures ◽  
Stimulation Of

Liquid cultures of bone marrow cells enriched for megakaryocytes were assayed for incorporation of 3H-thymidine (3H-TdR) into acid-precipitable cell digests to determine the effect of thrombopoietin on DNA synthesis. As previously described, thrombopoietin was prepared by ammonium sulfate fractionation of pooled plasma obtained from thrombocytopenic rabbits. A control fraction was prepared from normal rabbit plasma. The thrombopoietic activity of these fractions was determined in vivo with normal rabbits as assay animals and the rate of incorporation of 75Se-selenomethionine into newly formed platelets as an index of thrombopoietic activity of the infused material. Guinea pig megakaryocytes were purified using bovine serum albumin gradients. Bone marrow cultures containing 1.5-3.0x104 cells and 31%-71% megakaryocytes were incubated 18 h in modified Dulbecco’s MEM containing 10% of the concentrated plasma fractions from either thrombocytopenic or normal rabbits. In other control cultures, 0.9% NaCl was substituted for the plasma fractions. 3H-TdR incorporation was measured after cells were incubated for 3 h with 1 μCi/ml. The protein fraction containing thrombopoietin-stimulating activity caused a 25%-31% increase in 3H-TdR incorporation over that in cultures which were incubated with the similar fraction from normal plasma and a 29% increase over the activity in control cultures to which 0.9% NaCl had been added. These data suggest that thrombopoietin stimulates DNA synthesis in megakaryocytes and that this tecnique may be useful in assaying thrombopoietin in vitro.

scholarly journals Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2276-2285 ◽  
Author(s):  
Maria De La Luz Sierra ◽  
Paola Gasperini ◽  
Peter J. McCormick ◽  
Jinfang Zhu ◽  
Giovanna Tosato
Keyword(s):  
Bone Marrow ◽  
Dna Sequences ◽  
Peripheral Blood ◽  
Cell Function ◽  
Myeloid Cell ◽  
Cxcr4 Expression ◽  
Negative Regulator ◽  
Hematopoietic Stem

The mechanisms underlying granulocyte-colony stimulating factor (G-CSF)–induced mobilization of granulocytic lineage cells from the bone marrow to the peripheral blood remain elusive. We provide evidence that the transcriptional repressor growth factor independence-1 (Gfi-1) is involved in G-CSF–induced mobilization of granulocytic lineage cells from the bone marrow to the peripheral blood. We show that in vitro and in vivo G-CSF promotes expression of Gfi-1 and down-regulates expression of CXCR4, a chemokine receptor essential for the retention of hematopoietic stem cells and granulocytic cells in the bone marrow. Gfi-1 binds to DNA sequences upstream of the CXCR4 gene and represses CXCR4 expression in myeloid lineage cells. As a consequence, myeloid cell responses to the CXCR4 unique ligand SDF-1 are reduced. Thus, Gfi-1 not only regulates hematopoietic stem cell function and myeloid cell development but also probably promotes the release of granulocytic lineage cells from the bone marrow to the peripheral blood by reducing CXCR4 expression and function.

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