Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype

Olivos, David J.; Alvarez, Marta B.; Cheng, Ying‐Hua; Hooker, R. Adam; Ciovacco, Wendy A.; Bethel, Monique; McGough, Haley; Yim, Christopher; Chitteti, Brahmananda R.; Eleniste, Pierre P.; Srour, Edward F.; Bruzzaniti, Angela; Fuchs, Robyn K.; Kacena, Melissa A.

doi:10.1002/jcb.25874

Cited by 9 publications

(6 citation statements)

References 54 publications

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“…A co-culture experiment of MKs with murine calvarial osteoblasts showed improvements in osteoblast proliferation by three- to six-fold, compared to control groups, osteoblasts cultured alone [ 114 ]. Other studies have demonstrated that MKs are vital in osteoclast formation [ 114 , 115 , 116 , 117 , 118 , 119 ]. In addition, osteoclasts are essential in bone remodeling and eliminate necrotic tissue in the early phases of bone repair [ 120 , 121 ].…”

Section: Inducing Mks Via Thrombopoietin: a Potential Therapy For Craniofacial Bone Defectsmentioning

confidence: 99%

“…TPO induce HSCs to differentiate into mature MKs which are ultimately producing platelets, Figure 2 [ 104 , 105 , 106 , 107 , 110 , 111 ]. Several studies demonstrate that MKs play a key role in osteoblast proliferation [ 108 , 112 , 113 , 114 , 115 ] and osteoclast formation [ 114 , 115 , 116 , 117 , 118 , 119 ]. Osteoblasts and osteoclasts are essential for bone remodeling and eliminating necrotic tissue in early bone repair [ 120 , 121 ].…”

Section: Introductionmentioning

confidence: 99%

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Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy

Aghali

2021

Cells

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Craniofacial bone defects can result from various disorders, including congenital malformations, tumor resection, infection, severe trauma, and accidents. Successfully regenerating cranial defects is an integral step to restore craniofacial function. However, challenges managing and controlling new bone tissue formation remain. Current advances in tissue engineering and regenerative medicine use innovative techniques to address these challenges. The use of biomaterials, stromal cells, and growth factors have demonstrated promising outcomes in vitro and in vivo. Natural and synthetic bone grafts combined with Mesenchymal Stromal Cells (MSCs) and growth factors have shown encouraging results in regenerating critical-size cranial defects. One of prevalent growth factors is Bone Morphogenetic Protein-2 (BMP-2). BMP-2 is defined as a gold standard growth factor that enhances new bone formation in vitro and in vivo. Recently, emerging evidence suggested that Megakaryocytes (MKs), induced by Thrombopoietin (TPO), show an increase in osteoblast proliferation in vitro and bone mass in vivo. Furthermore, a co-culture study shows mature MKs enhance MSC survival rate while maintaining their phenotype. Therefore, MKs can provide an insight as a potential therapy offering a safe and effective approach to regenerating critical-size cranial defects.

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Section: Inducing Mks Via Thrombopoietin: a Potential Therapy For Craniofacial Bone Defectsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy

Aghali

2021

Cells

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“…in regulating the activity of osteoblasts and osteoclasts [5][6][7][8]. One cell type of particular interest is the MK, which plays a role in the regulation of bone formation and bone resorption within the marrow cavity [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

“…Numerous mouse models have been made where MK numbers are increased. These mice also have greatly increased bone growth within the marrow cavity [9,10,[20][21][22][23][24][25][26][27]. Importantly, osteosclerosis has been documented in patients with megakaryocytoses [28,29].…”

Section: Introductionmentioning

confidence: 99%

Aging negatively impacts the ability of megakaryocytes to stimulate osteoblast proliferation and bone mass

Maupin

Himes

Plett

et al. 2019

Bone

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Osteoblast number and activity decreases with aging, contributing to the age-associated decline of bone mass, but the mechanisms underlying changes in osteoblast activity are not well understood. Here, we show that the age-associated bone loss critically depends on impairment of the ability of megakaryocytes (MKs) to support osteoblast proliferation. Co-culture of osteoblast precursors with young MKs is known to increase osteoblast proliferation and bone formation. However, co-culture of osteoblast precursors with aged MKs resulted in significantly fewer osteoblasts compared to co-culture with young MKs, and this was associated with the downregulation of transforming growth factor beta. In addition, the ability of MKs to increase bone mass was attenuated during aging as transplantation of GATA1 low/low hematopoietic donor cells (which have elevated MKs/MK precursors) from young mice resulted in an increase in bone mass of recipient mice compared to transplantation of young wild-type donor cells, whereas transplantation of GATA1 low/low donor cells from old mice failed to enhance bone mass in recipient mice compared to transplantation of old wild-type donor cells. These findings suggest that the preservation or restoration of the MK-mediated induction of osteoblast proliferation during aging may hold the potential to prevent age-associated bone loss and resulting fractures.

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“…Regarding bone formation, several animal models with increased MK have also shown to exhibit increased bone formation 16 ; the increased osteoblast proliferation by MKs mainly mediated it [16][17][18] . Eventually, the mouse models with increased MK number exhibited the osteosclerotic phenotype 12,16,[19][20][21][22][23][24][25] . Thus, MK plays an of trabecular bone, regions of interest (ROI) of cancellous bone were created within the endosteal envelope on the two-dimensional slices.…”

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confidence: 99%

Regulation of bone metabolism by megakaryocytes in a paracrine manner

Lee

Kwak

Moon

et al. 2020

Sci Rep

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Megakaryocytes (MKs) play key roles in regulating bone metabolism.To test the roles of MK-secreted factors, we investigated whether MK and promegakaryocyte (pro-MK) conditioned media (CM) may affect bone formation and resorption. K562 cell lines were differentiated into mature MKs. Mouse bone marrow macrophages were differentiated into mature osteoclasts, and MC3T3-E1 cells were used for osteoblastic experiments. Bone formation was determined by a calvaria bone formation assay in vivo. Micro-CT analyses were performed in the femurs of ovariectomized female C57B/L6 and Balb/c nude mice after intravenous injections of MK or pro-MK CM. MK CM significantly reduced in vitro bone resorption, largely due to suppressed osteoclastic resorption activity. Compared with pro-MK CM, MK CM suppressed osteoblastic differentiation, but stimulated its proliferation, resulting in stimulation of calvaria bone formation. In ovariectomized mice, treatment with MK CM for 4 weeks significantly increased trabecular bone mass parameters, such as bone volume fraction and trabecular thickness, in nude mice, but not in C57B/L6 mice. In conclusion, MKs may secrete anti-resorptive and anabolic factors that affect bone tissue, providing a novel insight linking MKs and bone cells in a paracrine manner. New therapeutic agents against metabolic bone diseases may be developed from MK-secreted factors.Bone metabolism is regulated mainly by the action of bone-resorbing osteoclasts and bone-forming osteoblasts. Increased bone resorption and/or decreased bone formation can lead to reduced bone mass and quality, resulting in high fracture risk. Typical conditions that induce this imbalance include estrogen deficiency and immobilization 1,2 . On the contrary, decreased bone resorption and/or increased formation with pharmacological interventions can reverse these imbalances. Synchronously inhibiting bone resorption and stimulating bone formation are regarded as an ideal therapeutic strategy against metabolic bone diseases, such as osteoporosis.Bone marrow, where most osteoclasts and osteoblasts exist, also contains many types of hematopoietic cells. The coexistence of the cells in the bone marrow allows these cells to influence one another by cell-to-cell contact or in a paracrine manner. Specifically, megakaryocytes (MKs), as one of hematopoietic cell residing in bone marrow, have been intriguing in the field of bone research. MKs, which are polyploid cells derived from MK/erythroid progenitors, generate platelets, which contribute to hemostasis and produce a number of growth factors 3-5 . Interestingly, estrogen deficiency and immobilization reduced the number of MKs 6,7 , and estrogen treatment increased MK number in postmenopausal women 8 . In addition, MK-related disorders are associated with osteosclerosis 9-11 . Thus, MKs may have a critical role in bone metabolism.Actually, it has been reported that MKs may act on both bone resorption and bone formation. A mouse model with increased MKs showed decreased osteoclast number and bone resorption 12 . ...

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Lnk Deficiency Leads to TPO-Mediated Osteoclastogenesis and Increased Bone Mass Phenotype

Cited by 9 publications

References 54 publications

Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy

Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy

Aging negatively impacts the ability of megakaryocytes to stimulate osteoblast proliferation and bone mass

Regulation of bone metabolism by megakaryocytes in a paracrine manner

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