RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis

Iwaniec, Urszula T.; Turner, Russell T.; Lin, Yi; Clarke, B.L.; Gingery, Anne; Li, Wei

doi:10.1172/jci.insight.90517

Cited by 18 publications

(14 citation statements)

References 47 publications

(51 reference statements)

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“…SMCs are believed to play an active role in plaque mineralization through their release of calcifying matrix vesicles and their osteogenic differentiation ability [ 33 – 35 ]. Macrophages have also been reported to play a supportive role in plaque mineralization through the release of matrix vesicles and by their lineage with osteoclastic cells [ 36 – 38 ]. A more thorough histological with multiple co-stainings would attest the real phenotype of macrophages and smooth muscle cells present in each lesion, as CD68 and SMA can be also expressed at lesser levels by other myeloid and mesenchymal-derived cell types, respectively, and with respect with recent work suggesting that SMC could even transdifferentiate into macrophage-like cells [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification

et al. 2018

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Vascular calcification is a strong and independent predictive factor for cardiovascular complications and mortality. Our previous work identified important discrepancies in plaque composition and calcification types between carotid and femoral arteries. The objective of this study is to further characterize and understand the heterogeneity in vascular calcification among vascular beds, and to identify molecular mechanisms underlying this process. We established ECLAGEN biocollection that encompasses human atherosclerotic lesions and healthy arteries from different locations (abdominal, thoracic aorta, carotid, femoral, and infrapopliteal arteries) for histological, cell isolation, and transcriptomic analysis. Our results show that lesion composition differs between these locations. Femoral arteries are the most calcified arteries overall. They develop denser calcifications (sheet-like, nodule), and are highly susceptible to osteoid metaplasia. These discrepancies may derive from intrinsic differences between SMCs originating from these locations, as microarray analysis showed specific transcriptomic profiles between primary SMCs isolated from each arterial bed. These molecular differences translated into functional disparities. SMC from femoral arteries showed the highest propensity to mineralize due to an increase in basal TGFβ signaling. Our results suggest that biological heterogeneity of resident vascular cells between arterial beds, reflected by our transcriptomic analysis, is critical in understanding plaque biology and calcification, and may have strong implications in vascular therapeutic approaches.

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Section: Discussionmentioning

confidence: 99%

Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification

et al. 2018

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“…Micro‐computed tomography (µCT) was performed on the left femora and third lumbar vertebrae (LV3) of each mouse following overnight fixation with 10% neutral buffered formalin. µCT was completed as previously described (Lee et al, 2017; Philbrick, Turner, Branscum, Wong, & Iwaniec, 2015). Briefly, femora were scanned using a Scanco μCT40 scanner (Scanco Medical AG, Basserdorf, Switzerland) at a voxel size of 12 × 12 × 12 μm (55 kVp x‐ray voltage, 145 μA intensity, and 200 ms integration time).…”

Section: Methodsmentioning

confidence: 99%

“…Histomorphometry was completed as previously described (Iwaniec, Wronski, & Turner, 2008; Lee et al, 2017). In brief, distal femora were dehydrated, embedded undecalcified, and sectioned longitudinally.…”

Section: Methodsmentioning

confidence: 99%

Sclerostin antibody treatment rescues the osteopenic bone phenotype of TGFβ inducible early gene‐1 knockout female mice

Gingery

Subramaniam

Pitel

et al. 2020

Journal Cellular Physiology

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Deletion of TGFβ inducible early gene‐1 (TIEG) in mice results in an osteopenic phenotype that exists only in female animals. Molecular analyses on female TIEG knockout (KO) mouse bones identified increased expression of sclerostin, an effect that was confirmed at the protein level in serum. Sclerostin antibody (Scl‐Ab) therapy has been shown to elicit bone beneficial effects in multiple animal model systems and human clinical trials. For these reasons, we hypothesized that Scl‐Ab therapy would reverse the low bone mass phenotype of female TIEG KO mice. In this study, wildtype (WT) and TIEG KO female mice were randomized to either vehicle control (Veh, n = 12/group) or Scl‐Ab therapy (10 mg/kg, 1×/wk, s.c.; n = 12/group) and treated for 6 weeks. Following treatment, bone imaging analyses revealed that Scl‐Ab therapy significantly increased cancellous and cortical bone in the femur of both WT and TIEG KO mice. Similar effects also occurred in the vertebra of both WT and TIEG KO animals. Additionally, histomorphometric analyses revealed that Scl‐Ab therapy resulted in increased osteoblast perimeter/bone perimeter in both WT and TIEG KO animals, with a concomitant increase in P1NP, a serum marker of bone formation. In contrast, osteoclast perimeter/bone perimeter and CTX‐1 serum levels were unaffected by Scl‐Ab therapy, irrespective of mouse genotype. Overall, our findings demonstrate that Scl‐Ab therapy elicits potent bone‐forming effects in both WT and TIEG KO mice and effectively increases bone mass in female TIEG KO mice.

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“…Any abnormal bone remodeling process causes various skeletal disorders, such as osteoporosis, osteonecrosis, and osteolysis 3 . These diseases would deteriorate the bone microarchitecture, decrease the bone mass, and ultimately increase fracture risk 4 . As the only cell type well accepted to resorb bone in the human body, OCs have a key role in skeletal health.…”

Section: Introductionmentioning

confidence: 99%

“…OCs are multinucleated giant cells that originate from mononuclear myeloid hematopoietic stem cells of bone marrow and are formed by the fusion of multiple monocytes/macrophages 5 . Macrophage colony-stimulating factor (M-CSF) activation of its receptor c-Fms and RANKL activation of its receptor RANK are important signaling events that prompt OC precursors proliferation and differentiation 4 . RANKL signaling activates transcription factors, such as NF-κB, NFATc1, c-Fos, and calcineurin (CN), through triggering various downstream MAPK signaling cascades, such as p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) pathways, to upregulate OC functional genes, such as TRAP and Ctsk, which are considered the readouts of OC bone resorption and the marker genes of OCs 2,[5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

QKI deficiency leads to osteoporosis by promoting RANKL-induced osteoclastogenesis and disrupting bone metabolism

Zhao

Zhu

et al. 2020

Cell Death Dis

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Quaking (QKI), an RNA-binding protein, has been reported to exhibit numerous biological functions, such as mRNA regulation, cancer suppression, and anti-inflammation. However, little known about the effects of QKI on bone metabolism. In this study, we used a monocyte/macrophage-specific QKI knockout transgenic mouse model to investigate the effects of QKI deficiency on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis. The loss of QKI promoted the formation of multinucleated tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) from bone marrow macrophages, and upregulated the expression of OC-specific markers, including TRAP (Acp5) and cathepsin K (Ctsk). The pro-osteoclastogenesis effect of QKI deficiency was achieved by amplifying the signaling cascades of the NF-κB and mitogen-activated protein kinase (MAPK) pathways; then, signaling upregulated the activation of nuclear factor of activated T cells c1 (NFATc1), which is considered to be the core transcription factor that regulates OC differentiation. In addition, QKI deficiency could inhibit osteoblast (OB) formation through the inflammatory microenvironment. Taken together, our data suggest that QKI deficiency promoted OC differentiation and disrupted bone metabolic balance, and eventually led to osteopenia under physiological conditions and aggravated the degree of osteoporosis under pathological conditions.

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RIP140 in monocytes/macrophages regulates osteoclast differentiation and bone homeostasis

Cited by 18 publications

References 47 publications

Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification

Implication of molecular vascular smooth muscle cell heterogeneity among arterial beds in arterial calcification

Sclerostin antibody treatment rescues the osteopenic bone phenotype of TGFβ inducible early gene‐1 knockout female mice

QKI deficiency leads to osteoporosis by promoting RANKL-induced osteoclastogenesis and disrupting bone metabolism

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