TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors

Ansalone, Cecilia; Cole, John; Chilaka, Sabarinadh; Sunzini, Flavia; Sood, Shatakshi; Robertson, Jamie; Siebert, Stefan; McInnes, Iain B.; Goodyear, Carl S.

doi:10.1136/annrheumdis-2020-219262

Cited by 9 publications

(11 citation statements)

References 44 publications

(40 reference statements)

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“…Of note, also human terminally differentiated peripheral cDCs have a robust capacity to differentiate into bone resorbing OCs, suggesting that also in humans DCs possibly contribute to OCs. The recently described CD11c + myeloid cells with osteoclastogenic potential are possibly overlapping with our CD1c + cDC population, highlighting the potential of DC like cells as OC precursors 47…”

Section: Discussionsupporting

confidence: 71%

Bona fide dendritic cells are pivotal precursors for osteoclasts

Puchner,

Simader,

Saferding

et al. 2023

Ann Rheum Dis

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ObjectivesOsteoclasts (OCs) are myeloid-derived multinucleated cells uniquely able to degrade bone. However, the exact nature of their myeloid precursors is not yet defined.MethodsCD11c-diphtheria toxin receptor (CD11cDTR) transgenic mice were treated with diphtheria toxin (DT) or phosphate buffered saline (PBS) during serum transfer arthritis (STA) and human tumour necrosis factor transgenic (hTNFtg) arthritis and scored clinically and histologically. We measured cytokines in synovitis by quantitative polymerase chain reaction (qPCR). We performed ovariectomy in CD11cDTR mice treated with PBS or DT. We analysed CD11cDTR, CD11c-Cre/CX3CR1-STOP-DTR and Zbtb46-DTR-treated mice with DT using histomorphometry and OC of CD11c and Zbtb46 fate reporter mice by fluorescent imaging. We sorted murine and human OC precursors and stimulated them with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL) to generate OCs.ResultsTargeting CD11c+cells in vivo in models of inflammatory arthritis (STA and hTNFtg) ameliorates arthritis by reducing inflammatory bone destruction and OC generation. Targeting CD11c-expressing cells in unchallenged mice removes all OCs in their long bones. OCs do not seem to be derived from CD11c+cells expressing CX3CR1+, but from Zbtb46+conventional dendritic cells (cDCs) as all OCs in Zbtb46-Tomato fate reporter mice are Tomato+. In line, administration of DT in Zbtb46-DTR mice depletes all OCs in long bones. Finally, human CD1c-expressing cDCs readily differentiated into bone resorbing OCs.ConclusionTaken together, we identify DCs as important OC precursors in bone homeostasis and inflammation, which might open new avenues for therapeutic interventions in OC-mediated diseases.

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Section: Discussionsupporting

confidence: 71%

Bona fide dendritic cells are pivotal precursors for osteoclasts

Puchner,

Simader,

Saferding

et al. 2023

Ann Rheum Dis

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“…In humans, three subpopulations of MN-derived OCPs have been described: classical MNs (CD14 + CD16 − ), 14 intermediate MNs (CD14 high CD16 + ), 129 , 130 and a circulating myeloid population (CD14 − CD16 − CD11c + ). 131 …”

Section: Part II Diversity Of Osteoclast Precursors In Chronic Inflam...mentioning

confidence: 99%

“…The circulating CD14 − CD16 − CD11c + myeloid population rapidly differentiated into more numerous and larger OCs than those differentiated from CD14 + OCPs. 131 It was reported that 56% of patients with moderate-to-severe active RA were unresponsive to TNF-α treatment because TNF-α inhibited osteoclastic differentiation of classical or intermediate MN OCPs (CD14 + ) but not myeloid OCPs (CD11c + ). 131 …”

Section: Part II Diversity Of Osteoclast Precursors In Chronic Inflam...mentioning

confidence: 99%

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New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis

et al. 2023

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Rheumatoid arthritis (RA) and periodontitis are chronic inflammatory diseases leading to increased bone resorption. Preventing this inflammatory bone resorption is a major health challenge. Both diseases share immunopathogenic similarities and a common inflammatory environment. The autoimmune response or periodontal infection stimulates certain immune actors, leading in both cases to chronic inflammation that perpetuates bone resorption. Moreover, RA and periodontitis have a strong epidemiological association that could be explained by periodontal microbial dysbiosis. This dysbiosis is believed to be involved in the initiation of RA via three mechanisms. (i) The dissemination of periodontal pathogens triggers systemic inflammation. (ii) Periodontal pathogens can induce the generation of citrullinated neoepitopes, leading to the generation of anti-citrullinated peptide autoantibodies. (iii) Intracellular danger-associated molecular patterns accelerate local and systemic inflammation. Therefore, periodontal dysbiosis could promote or sustain bone resorption in distant inflamed joints. Interestingly, in inflammatory conditions, the existence of osteoclasts distinct from “classical osteoclasts” has recently been reported. They have proinflammatory origins and functions. Several populations of osteoclast precursors have been described in RA, such as classical monocytes, a dendritic cell subtype, and arthritis-associated osteoclastogenic macrophages. The aim of this review is to synthesize knowledge on osteoclasts and their precursors in inflammatory conditions, especially in RA and periodontitis. Special attention will be given to recent data related to RA that could be of potential value in periodontitis due to the immunopathogenic similarities between the two diseases. Improving our understanding of these pathogenic mechanisms should lead to the identification of new therapeutic targets involved in the pathological inflammatory bone resorption associated with these diseases.

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“…This method aimed to easily differentiate a large number of OCs from human peripheral blood CD14 + monocytes in vitro, typically in 1 week. Firstly, CD14 + monocytes were enriched from PBMCs and primed with M-CSF overnight to upregulate RANK, as previously reported 15 . Following monocyte priming, to determine the optimum concentration of RANKL for OC differentiation and maturation, RANKL concentrations of 1 ng/mL, 25 ng/mL, 50 ng/mL, and 100 ng/mL, along with 25ng/mL M-CSF, were used.…”

Section: Oc Generation From Cd14 + Monocytesmentioning

confidence: 99%

Differentiation of Functional Osteoclasts from Human Peripheral Blood CD14<sup>+</sup> Monocytes

Riedlova

Sood

Goodyear

et al. 2023

JoVE

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Osteoclasts (OCs) are bone-resorbing cells that play a pivotal role in skeletal development and adult bone remodeling. Several bone disorders are caused by increased differentiation and activation of OCs, so the inhibition of this pathobiology is a key therapeutic principle.Two key factors drive the differentiation of OCs from myeloid precursors: macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL). Human circulating CD14 + monocytes have long been known to differentiate into OCs in vitro. However, the exposure time and the concentration of RANKL influence the differentiation efficiency. Indeed, protocols for the generation of human OCs in vitro have been described, but they often result in a poor and lengthy differentiation process. Herein, a robust and standardized protocol for generating functionally active mature human OCs in a timely manner is provided. CD14 + monocytes are enriched from human peripheral blood mononuclear cells (PBMCs) and primed with M-CSF to upregulate RANK. Subsequent exposure to RANKL generates OCs in a dose-and time-dependent manner. OCs are identified and quantified by staining with tartrate acid-resistant phosphatase (TRAP) and light microscopy analysis. Immunofluorescence staining of nuclei and F-actin is used to identify functionally active OCs. In addition, OSCAR + CD14 − mature OCs are further enriched via flow cytometry cell sorting, and OC functionality quantified by mineral (or dentine/bone) resorption assays and actin ring formation. Finally, a known OC inhibitor, rotenone, is used on mature OCs, demonstrating that adenosine triphosphate (ATP) production is essential for actin ring integrity and OC function. In conclusion, a robust assay for differentiating high numbers of OCs is established in this work, which in combination with actin ring staining and an ATP assay provides a useful in vitro model to evaluate OC function and to screen for novel therapeutic compounds that can modulate the differentiation process.

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TNF is a homoeostatic regulator of distinct epigenetically primed human osteoclast precursors

Cited by 9 publications

References 44 publications

Bona fide dendritic cells are pivotal precursors for osteoclasts

Bona fide dendritic cells are pivotal precursors for osteoclasts

New insights into inflammatory osteoclast precursors as therapeutic targets for rheumatoid arthritis and periodontitis

Differentiation of Functional Osteoclasts from Human Peripheral Blood CD14<sup>+</sup> Monocytes

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