Hdac3 Deficiency Increases Marrow Adiposity and Induces Lipid Storage and Glucocorticoid Metabolism in Osteochondroprogenitor Cells

McGee‐Lawrence, Meghan E.; Carpio, Lomeli R.; Schulze, Ryan J.; Pierce, Jessica L.; McNiven, Mark A.; Farr, Joshua N.; Khosla, Sundeep; Oursler, Merry Jo; Westendorf, Jennifer J.

doi:10.1002/jbmr.2602

Cited by 61 publications

(62 citation statements)

References 88 publications

(189 reference statements)

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“…We and others have observed that, in addition to being highly active in cartilage, the Col2ERT-Cre driver is also active in a subset of bone marrow mesenchymal progenitor cells, lining cells, and osteocytes (fig. S11A) (59–61). IL-6 is normally produced by cells in these regions but did not appear to be as drastically increased there in Hdac3 -CKO Col2ERT mice as compared to its aberrant presence in the growth plate (fig.…”

Section: Resultsmentioning

confidence: 99%

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

et al. 2016

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Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen α1 (Col2α1)–expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor κB (NF-κB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and NF-κB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)–JAK–STAT signaling, NF-κB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development.

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Section: Resultsmentioning

confidence: 99%

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

et al. 2016

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“…The treatment with a HDAC inhibitor promotes osteoblastogenesis [57–63] and also increases genome-wide distribution of H4 acetylation [64]. A conditional deletion of HDAC3 in osteochondroprogenitor cells results in osteopenia and increases marrow adiposity [65]. Resveratrol or isonicotinamide is an agonist of Sirtuin 1, class III HDAC, and blocks spontaneous adipocyte differentiation and thereby promotes osteoblast differentiation and bone mineralization [66].…”

Section: Histone Modificationmentioning

confidence: 99%

Epigenetic regulation of bone cells

Park-Min

2016

Connective Tissue Research

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Bone is a major organ in the skeletal system that supports and protects muscle and other organs, facilitates movement and hematopoiesis, and forms a reservoir of minerals including calcium. The cells in the bone, such as osteoblasts, osteoclasts, and osteocytes, orchestrate sequential and balanced regulatory mechanisms to maintain bone and are capable of differentiating in bones. Bone development and remodeling require a precise regulation of gene expressions in bone cells, a process governed by epigenetic mechanisms such as histone modification, DNA methylation, and chromatin structure. Importantly, lineage-specific transcription factors can determine the epigenetic regulation of bone cells. Emerging data suggest that perturbation of epigenetic programs can affect function and activity of bone cells and contributes to pathogenesis of bone diseases, including osteoporosis. Thus, understanding epigenetic regulations in bone cells would be important for early diagnosis and future therapeutic approaches.

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“…Indeed, osterix positive marrow adipocytes have been shown in lineage tracing studies, and marrow adipocytes can be traced to peroxiredoxin 1 (Rosen, personal communication). Moreover, some Runx2-positive cells isolated in high marrow adiposity states also have large lipid droplets and express perilipin (49). …”

Section: Relationship Between the Osteo/adipogenic Processes The Obesmentioning

confidence: 99%

Qualitative Aspects of Bone Marrow Adiposity in Osteoporosis

et al. 2016

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The function of marrow adipocytes and their origin has not been defined although considerable research has centered on their presence in certain conditions, such as osteoporosis. Less work has focused on the qualitative aspects of marrow fat. Bone marrow serum is composed of multiple nutrients that almost certainly relate to functional aspects of the niche. Previous studies using non-invasive techniques have shown that osteoporotic individuals have more marrow fat and that the ratio of saturated: unsaturated fatty acid is high. We recently reported that bone marrow sera from osteoporotic patients with fracture showed a switch toward decreased content of total saturated versus unsaturated fatty acids, compared to patients without fracture highlighting a dynamic relationship between the composition of fatty acids in the bone microenvironment and the metabolic requirements of cells. The relative distribution of fatty acids differed considerably from that in the serum providing further evidence that energy utilization is high and that marrow adipocytes may contribute to this pool. Whether these lipids can affect osteoblast function in a positive or negative manner is still not certain but will require further investigation.

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Hdac3 Deficiency Increases Marrow Adiposity and Induces Lipid Storage and Glucocorticoid Metabolism in Osteochondroprogenitor Cells

Cited by 61 publications

References 88 publications

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

Epigenetic regulation of bone cells

Qualitative Aspects of Bone Marrow Adiposity in Osteoporosis

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