Age-related Marrow Adipogenesis Is Linked to Increased Expression of RANKL

Takeshita, Satoshi; Fumoto, Toshio; Naoe, Yoshinori; Ikeda, Kyoji

doi:10.1074/jbc.m114.547919

Cited by 123 publications

(85 citation statements)

References 42 publications

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“…It is of note that Sinha et al also reported that Gsα OsxKO bones showed an 8-fold increase in Pref-1 expression, a marker of pre-adipocytes, compared to controls (Sinha et al, 2014). And previously, Takeshita et al noted that in aging mouse marrow, with significant adiposity, the proportion of RANKL + /Pref1 + cells was markedly increased (Takeshita et al, 2014). In addition, we noted that BMSCs derived from the mutants when grown in osteogenic, adipogenic or no differentiation media, expressed consistently higher levels of Rankl and greater Rankl/Opg ratios than controls (Figure S6A).…”

Section: Discussionmentioning

confidence: 94%

“…To further characterize RANKL positive cells in the bone marrow we performed extensive flow cytometry using the RANKL antibody in combination with Pref-1 as the marker of pre-adipocytes (Takeshita et al, 2014) and B220 as a B cell lineage marker (Figure 6) (Smas and Sul, 1993). FACS analysis revealed that in B220 negative cells, the percentage of Pref-1 positive cells was increased in Prx1Cre;PTH1R fl/fl , Tm fl/+ mice compared to control heterozygous littermates (Figure 6A left, Q1+Q2).…”

Section: Resultsmentioning

confidence: 99%

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Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

et al. 2017

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Summary Intermittent PTH administration builds bone mass and prevents fractures, but its mechanism of action is unclear. We genetically deleted the PTH/PTHrP Receptor (PTH1R) in mesenchymal stem cells using Prx1Cre and found low bone formation, increased bone resorption and high bone marrow adipose tissue (BMAT). Bone marrow adipocytes traced to Prx1 and expressed classic adipogenic markers and high receptor activator of nuclear factor kappa-B ligand (Rankl) expression. RANKL levels were also elevated in bone marrow supernatant and serum, but undetectable in other adipose depots. By cell sorting, Pref1+RANKL+ marrow progenitors were twice as great in mutant versus control marrow. Intermittent PTH administration to control mice reduced BMAT significantly. A similar finding was noted in male osteoporotics. Thus, marrow adipocytes exhibit osteogenic and adipogenic characteristics, are uniquely responsive to PTH, and secrete RANKL. These studies reveal an important mechanism for PTH’s therapeutic action through its ability to direct mesenchymal cell fate.

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Section: Discussionmentioning

confidence: 94%

Section: Resultsmentioning

confidence: 99%

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

et al. 2017

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“…These cells also show enlargement, telomere shortening, or p53/p21-mediated DNA damage accumulation, impaired DNA methylation or histone acetylation, and increased levels of ROS and nitric oxide (NO) (65–69). Although age-dependent mechanisms underlying adipogenesis-favoring MSC differentiation are not as yet fully understood, possible molecular changes have been reported, including activations of peroxisome proliferator-activated receptor gamma 2 and CCAAT/enhancer binding protein (70, 71). Adipogenesis enhancement in aged BM (72) might be linked to dysregulation of insulin growth factor signaling (27), changes in extracellular matrix composition, and decreased bone formation (73, 74).…”

Section: Hematopoietic Agingmentioning

confidence: 99%

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

et al. 2016

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All hematopoietic and immune cells are continuously generated by hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) through highly organized process of stepwise lineage commitment. In the steady state, HSCs are mostly quiescent, while HPCs are actively proliferating and contributing to daily hematopoiesis. In response to hematopoietic challenges, e.g., life-threatening blood loss, infection, and inflammation, HSCs can be activated to proliferate and engage in blood formation. The HSC activation induced by hematopoietic demand is mediated by direct or indirect sensing mechanisms involving pattern recognition receptors or cytokine/chemokine receptors. In contrast to the hematopoietic challenges with obvious clinical symptoms, how the aging process, which involves low-grade chronic inflammation, impacts hematopoiesis remains undefined. Herein, we summarize recent findings pertaining to functional alternations of hematopoiesis, HSCs, and the bone marrow (BM) microenvironment during the processes of aging and inflammation and highlight some common cellular and molecular changes during the processes that influence hematopoiesis and its cells of origin, HSCs and HPCs, as well as the BM microenvironment. We also discuss how age-dependent alterations of the immune system lead to subclinical inflammatory states and how inflammatory signaling might be involved in hematopoietic aging. Our aim is to present evidence supporting the concept of “Inflamm-Aging,” or inflammation-associated aging of hematopoiesis.

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“…Paraffin-embedded BM biopsy specimens were stained with H&E and for Pref-1, a welldescribed marker for preadipocytes. 18,20 Balloon-like mature adipocytes and Pref-1epositive preadipocytes were enumerated. The results revealed significantly greater Pref1epositive cells in the BM of patients with MM compared with healthy BM, indicating an increase in the preadipocyte population in MM patients ( Figure 1, A and B).…”

Section: Patients With MM Have Enhanced Bone Marrow Adipogenesismentioning

confidence: 99%

Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone

Trotter

Gibson

Lama-Sherpa

et al. 2016

The American Journal of Pathology

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Multiple myeloma (MM) cells reside in the bone marrow microenvironment and form complicated interactions with nonneoplastic, resident stromal cells. We previously found that aggressive MM cells shift osteoblast progenitors toward adipogenesis. In addition, adipocytes are among the most common cell types in the adult skeleton; both mature adipocytes and preadipocytes serve as endocrine cells that secrete a number of soluble molecules into the microenvironment. Therefore, we used a combination of in vivo and in vitro methods to test the hypothesis that an increase in adipocyte lineage cells feeds back to promote MM progression. The results of this study revealed that bone marrow from patients with MM indeed contains increased preadipocytes and significantly larger mature adipocytes than normal bone marrow. We also found that preadipocytes and mature adipocytes secrete many molecules important for supporting MM cells in the bone marrow and directly recruit MM cells through both monocyte chemotactic protein-1 and stromal cell-derived factor-1a. Co-culture experiments found that preadipocytes activate Wnt signaling and decrease cleaved caspase-3, whereas mature adipocytes activate ERK signaling in MM cells. Furthermore, mature adipocyte conditioned medium promotes MM growth, whereas co-culture with preadipocytes results in enhanced MM cell chemotaxis in vitro and increased tumor growth in bone in vivo. Combined, these data reveal the importance of preadipocytes and mature adipocytes on MM progression and represent a unique target in the bone marrow microenvironment. (Am J Pathol 2016, 186: 3054e3063; http://dx

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Age-related Marrow Adipogenesis Is Linked to Increased Expression of RANKL

Cited by 123 publications

References 42 publications

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Parathyroid Hormone Directs Bone Marrow Mesenchymal Cell Fate

Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment

Adipocyte-Lineage Cells Support Growth and Dissemination of Multiple Myeloma in Bone

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