The effect of Activin‐A on periodontal ligament fibroblasts‐mediated osteoclast formation in healthy donors and in patients with fibrodysplasia ossificans progressiva

Schoenmaker, Ton; Wouters, Fenne; Micha, Dimitra; Forouzanfar, Tim; Netelenbos, Coen; Eekhoff, Elisabeth M. W.; Bravenboer, Nathalie; Vries, Teun J. de

doi:10.1002/jcp.27693

Cited by 13 publications

(17 citation statements)

References 38 publications

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“…In contrast, Fowler et al [23] reported that activin A completely inhibited RANKL-stimulated osteoclast motility, differentiation, and bone resorption in stroma-free murine bone marrow macrophage cultures. Recently, Schoenmaker et al [37] reported that activin A inhibits osteoclast formation stimulated with periodontal ligament fibroblasts from patients with fibrodysplasia ossificans progressiva, which is a genetic disease characterized by a mutation in the activin receptor type 1 (ACVR1) gene that results in enhanced responsiveness of the receptor to activin A. Moreover, consistent with our results, activin A inhibited RANKL-induced osteoclastogenesis in monocultures of CD14+ monocytes [37].…”

Section: Discussionsupporting

confidence: 90%

“…Recently, Schoenmaker et al [37] reported that activin A inhibits osteoclast formation stimulated with periodontal ligament fibroblasts from patients with fibrodysplasia ossificans progressiva, which is a genetic disease characterized by a mutation in the activin receptor type 1 (ACVR1) gene that results in enhanced responsiveness of the receptor to activin A. Moreover, consistent with our results, activin A inhibited RANKL-induced osteoclastogenesis in monocultures of CD14+ monocytes [37]. The discrepancy between the reported effects of activin A on osteoclastogenesis may be due to differences between species or culture systems.…”

Section: Discussionmentioning

confidence: 99%

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Activin A Expressed in Rheumatoid Synovial Cells Downregulates TNFα-Induced CXCL10 Expression and Osteoclastogenesis

Kuranobu

Mokuda

et al. 2020

Pathobiology

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Objective: Activin A is known to be highly expressed in rheumatoid synovium. In the present study, we investigated the effect of inflammatory cytokines on activin A production and its role in rheumatoid inflammation using freshly prepared rheumatoid synovial cells (fresh-RSC). Methods: Fresh-RSC from patients with rheumatoid arthritis were obtained and stimulated with multiple cytokines for activin A production. Gene expression levels of activin A and inflammatory cytokines were determined by quantitative PCR (qPCR) analysis. An enzyme-linked immunosorbent assay (ELISA) was used to measure activin A and CXCL10 in culture supernatants. The osteoclasts generated from human peripheral monocytes by RANKL stimulation were identified by tartrate-resistant acid phosphatase staining and bone resorption assay using Osteo plate. The expression levels of NFATc1 and cathepsin K, critical intracellular proteins for osteoclastogenesis, were determined by Western blotting. Results: Activin A production in fresh-RSC was markedly enhanced by the synergistic effect of TGF-β₁ with inflammatory cytokines, including TNFα, IL-1β, and IL-6. Activin A inhibited TNFα-induced CXCL10, an important chemoattractant for pathogen-activated T cells and monocytes of osteoclast precursors, but it did not affect the expression of inflammatory cytokines and chemokines. In addition, activin A directly inhibited the expression of NFATc1 and cathepsin K, as well as osteoclast formation in human samples. Conclusion: Our data indicated that TGF-β₁ is involved in the expression of activin A at inflamed joints. Activin A mainly exerts an anti-inflammatory action, which prevents joint damage via the regulation of CXCL10 and osteoclastogenesis.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Activin A Expressed in Rheumatoid Synovial Cells Downregulates TNFα-Induced CXCL10 Expression and Osteoclastogenesis

Kuranobu

Mokuda

et al. 2020

Pathobiology

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“…POF is caused by genetic mutations inducing osteogenic differentiation [14]. Two clinical features define classic POF: big toe malformations and progressive heterotopic endochondral ossifications in key anatomical areas (back, knees, and hands).…”

Section: Discussionmentioning

confidence: 99%

Characteristics of the odontological management of patients with progressive ossifying fibrodyplasia

Ibourk

Bouzoubaa

Yahya

2019

J Oral Med Oral Surg

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Introduction: Progressive ossifying fibrodysplasia (POF) is a rare autosomal dominant disease characterized by the congenital malformation of the big toes and progressive postnatal heterotopic ossification of soft tissues with characteristic anatomical profiles. The maxillofacial region may also be affected. Observation: A 24-year-old man was referred by a traumatologist for the restoration of the oral cavity. He showed characteristic signs of POF. Oral clinical examination showed limitation of the oral opening, multiple dental caries, dental necrosis, and an asymptomatic impacted 48. Management included motivation for oral hygiene, scaling and dental extractions, followed by a prescription of steroidal anti-inflammatory drugs at a single dose of 2 mg/kg/day for 4 days. Discussion: The management of patients with POF in oral surgery has particularities. Dental care must be performed in brief sessions. The patient must be in a semi-sitting position, with the neck held upright, to avoid hyper extension of the neck and to improve comfort and safety. A prescription for corticosteroids is necessary after dental care to prevent possible heterotopic ossification. Through this article, we highlight the characteristics of POF, therapeutic attitude, and precautions to take to avoid possible complications.

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“…When these PLF were cocultured with non-mutated CD14+ osteoclast precursors, no significant difference in PLF induced osteoclastogenesis between the control and FOP PLF was observed (18). In addition, adding Activin-A to these cocultures inhibited osteoclast formation regardless of the mutation in the PLF cells (19). This suggests a direct effect of Activin-A on the CD14+ osteoclast precursors.…”

Section: Introductionmentioning

confidence: 89%

Activin-A Induces Fewer, but Larger Osteoclasts From Monocytes in Both Healthy Controls and Fibrodysplasia Ossificans Progressiva Patients

Schoenmaker

Botman²,

Sariyildiz³

et al. 2020

Front. Endocrinol.

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Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disease characterized by heterotopic ossification (HO) that occurs in muscle tissue, tendons, and ligaments. The disease is caused by mutations in the Activin receptor type I (ACVR1) gene resulting in enhanced responsiveness to Activin-A. Binding of this molecule to the mutated receptor induces HO. Bone metabolism normally requires the coupled action of osteoblasts and osteoclasts, which seems to be disturbed during HO. We hypothesize that Activin-A may also counteract the formation of osteoclasts in FOP patients. In this study we investigated the effect of Activin-A on osteoclast differentiation of CD14+ monocytes from FOP patients and healthy controls. The lymphocytic and monocytic cell populations were determined by FACS analysis. Expression of the mutated R206H receptor was assessed and confirmed by allele specific PCR. The effect of Activin-A on osteoclastogenesis was assessed by counting the number and size of multinucleated cells. Osteoclast activity was determined by culturing the cells on Osteo Assay plates. The influence of Activin-A on expression of various osteoclast related genes was studied with QPCR. Blood from FOP patients contained similar percentages of classical, intermediate, or non-classical monocytes as healthy controls. Addition of Activin-A to the osteoclastogenesis cultures resulted in fewer osteoclasts in both control and FOP cultures. The osteoclasts formed in the presence of Activin-A were, however, much larger and more active compared to the cultures without Activin-A. This effect was tempered when the Activin-A inhibitor follistatin was added to the Activin-A containing cultures. Expression of osteoclast specific genes Cathepsin K and TRAcP was upregulated, gene expression of osteoclastogenesis related genes M-CSF and DC-STAMP was downregulated by Activin-A. Since Activin-A is a promising target for inhibiting the formation of HO in FOP, it is important to know its effects on both osteoblasts and osteoclasts. Our study shows that Activin-A induces fewer, but larger and more active osteoclasts independent of the presence of the mutated ACVR1 receptor. When considering FOP as an Activin-A driven disease that acts locally, Schoenmaker et al. Activin-A and Osteoclasts in FOP our findings suggest that Activin-A could cause a more pronounced local resorption by larger osteoclasts. Thus, when targeting Activin-A in patients with neutralizing antibodies, HO formation could potentially be inhibited, and osteoclastic activity could be slightly reduced, but then performed dispersedly by more and smaller osteoclasts.

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The effect of Activin‐A on periodontal ligament fibroblasts‐mediated osteoclast formation in healthy donors and in patients with fibrodysplasia ossificans progressiva

Cited by 13 publications

References 38 publications

Activin A Expressed in Rheumatoid Synovial Cells Downregulates TNFα-Induced CXCL10 Expression and Osteoclastogenesis

Activin A Expressed in Rheumatoid Synovial Cells Downregulates TNFα-Induced CXCL10 Expression and Osteoclastogenesis

Characteristics of the odontological management of patients with progressive ossifying fibrodyplasia

Activin-A Induces Fewer, but Larger Osteoclasts From Monocytes in Both Healthy Controls and Fibrodysplasia Ossificans Progressiva Patients

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