RCANs regulate the convergent roles of NFATc1 in bone homeostasis

Kim, Jung Ha; Kim, Kabsun; Kim, In-Young; Seong, Semun; Jeong, Byung‐Chul; Nam, Kwang Il; Kim, Kyung Keun; Molkentin, Jeffery D.; Kim, Nacksung

doi:10.1038/srep38526

Cited by 16 publications

(11 citation statements)

References 38 publications

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“…Also, mice deficient in NFATc1 exhibited defects in osteoclast differentiation and demonstrated symptoms of osteopetrosis 52 . Similarly, the inhibition of NFATc1 transcriptional activity attenuated RANKL osteoclastogenesis 53,54 . In the present study, we showed that C-PC significantly inhibited RANKL-induced c-Fos expression at the protein level.…”

Section: Discussionmentioning

confidence: 98%

C-phycocyanin attenuates RANKL-induced osteoclastogenesis and bone resorption in vitro through inhibiting ROS levels, NFATc1 and NF-κB activation

AlQranei

Aljohani

Majumdar

et al. 2020

Sci Rep

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Excessive bone loss occurs in inflammatory disorders such as periodontitis and osteoporosis. The underlying mechanism is related to the differentiation of macrophages into multinucleated giant osteoclasts and their bone resorptive activity. c-phycocyanin (c-pc) is a phycobiliprotein extracted from the blue-green algae, which has been shown to have various pharmacological effects. The role of C-PC on bone metabolism needs revelation. In this study, we determined the effectiveness of C-PC as an inhibitor of osteoclast differentiation, activity, and survival in vitro. We found that C-PC strongly inhibited the differentiation of macrophages to TRAP-positive osteoclasts, distinctive osteoclast specific podosomal organization, and dentine matrix resorption without any cytotoxicity. Also, it suppressed the expression of osteoclast specific markers, such as cathepsin K and integrin β3 at mRNA and protein levels. RANKL mediated signaling utilizes reactive oxygen species (ROS) for the differentiation of osteoclasts. C-PC attenuated RANKL stimulated ROS. Mechanistic studies indicate that C-PC has the potential to reduce osteoclast formation via blocking the degradation of cytosolic iκB-α and hence, the activation of downstream markers such as c-Fos and NFATc1. However, it does not have any effect on osteoblast-mediated bone formation in vitro. collectively, our data suggest that c-pc may be utilized as a therapeutic agent that can target bone loss mediated by excessive osteoclastic bone resorption without affecting osteoblastic activity in bone. Bone remodeling is a physiologically orchestrated process in which a simultaneous interplay between bone resorption and bone formation facilitates the development and maintenance of the skeletal tissues. However, an abnormal increased or decreased bone resorption rate is involved in the pathophysiology of multiple skeletal disorders 1,2. Osteolytic diseases, such as osteoporosis and periodontitis, carry a serious health concern. The net outcome of such pathological conditions is the loss of healthy and supportive bone due to the activation of osteoclasts 3,4. Osteoclasts are multinucleated-giant cells that are functionally recognized as primary bone-resorbing cells. Osteoclasts express tartrate-resistant acid phosphatase (TRAP), which is considered as one of the biomarkers. Osteoclasts are highly migratory cells, and their migration is dependent on rapid changes in their actin cytoskeletal structures. Osteoclasts do not have the focal adhesion attachment structures typical of other cells 5. Osteoclasts plated on glass coverslips demonstrated discrete dot-like podosome structures at the periphery, and, in some cells, podosomes were observed as ring-like structures 6,7. These types of podosomal or actin-ring like structures represent the unique characteristics that can demarcate the mature osteoclasts from osteoclast precursors. Osteoclasts are highly migrated cells and dependent on podosomes for their cellular motility 6,8,9 .

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Section: Discussionmentioning

confidence: 98%

C-phycocyanin attenuates RANKL-induced osteoclastogenesis and bone resorption in vitro through inhibiting ROS levels, NFATc1 and NF-κB activation

AlQranei

Aljohani

Majumdar

et al. 2020

Sci Rep

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“…NFATc1 is well known as a master regulator of osteoclastogenesis (Kim et al, 2016) whilst the role of NFATc1 signaling in osteoblasts is not well understood and is still controversial (Kim et al, 2016; Penolazzi et al, 2011). Ca 2+ ‐NFATc1 signaling and NFAT transcriptional activity are previously demonstrated to be activated during rat osteoblastic mineralization by high ATP concentrations acting through P2X7R (Grol et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Expression and function of the P2X7 receptor in human osteoblasts: The role of NFATc1 transcription factor

Bergamin

Penolazzi

Lambertini

et al. 2020

Journal Cellular Physiology

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Bone mineralization is an orchestrated process by which mineral crystals are deposited by osteoblasts; however, the detailed mechanisms remain to be elucidated. The presence of P2X7 receptor (P2X7R) in immature and mature bone cells is well established, but contrasting evidence on its role in osteogenic differentiation and deposition of calcified bone matrix remains. To clarify these controversies in the present study, we investigated P2X7R participation in bone maturation. We demonstrated that the P2X7R is expressed and functional in human primary osteoblasts, and identified in the P2RX7 promoter several binding sites for transcription factors involved in bone mineralization. Of particular interest was the finding that P2X7R expression is enhanced by nuclear factor of activated T cells cytoplasmic 1 (NFATc1) overexpression, and accordingly, NFATc1 is recruited at the P2RX7 gene promoter in SaOS2 osteoblastic-like cells. In conclusion, our data provide further insights into the regulation of P2X7R expression and support the development of drugs targeting this receptor for the therapy of bone diseases.

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“…46 It is reported that disruption of RCAN2 could lead to reducing bone mass, which is related to increased osteoclast function and reduced osteoblast function. 47 IL9R is associated with hematopoietic cell lineage. 48 Our result indicated that hsa-let-7a-5p and its target (RCAN2 and IL9R) could be involved in osteonecrosis of the femoral head.…”

Section: Discussionmentioning

confidence: 99%

Identifying the Potential Differentially Expressed miRNAs and mRNAs in Osteonecrosis of the Femoral Head Based on Integrated Analysis

Hao

Lü

Zhang

et al. 2021

CIA

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Purpose Osteonecrosis of the femoral head is a common disease of the hip that leads to severe pain or joint disability. We aimed to identify potential differentially expressed miRNAs and mRNAs in osteonecrosis of the femoral head. Methods The data of miRNA and mRNA were firstly downloaded from the database. Secondly, the regulatory network of miRNAs–mRNAs was constructed, followed by function annotation of mRNAs. Thirdly, an in vitro experiment was applied to validate the expression of miRNAs and targeted mRNAs. Finally, GSE123568 dataset was used for electronic validation and diagnostic analysis of targeted mRNAs. Results Several regulatory interaction pairs between miRNA and mRNAs were identified, such as hsa-miR-378c-WNT3A/DACT1/CSF1, hsa-let-7a-5p-RCAN2/IL9R, hsa-miR-28-5p-RELA, hsa-miR-3200-5p-RELN, and hsa-miR-532-5p-CLDN18/CLDN10. Interestingly, CLDN10, CLDN18, CSF1, DACT1, IL9R, RCAN2, RELN, and WNT3A had the diagnostic value for osteonecrosis of the femoral head. Wnt signaling pathway (involved WNT3A), chemokine signaling pathway (involved RELA), focal adhesion and ECM-receptor interaction (involved RELN), cell adhesion molecules (CAMs) (involved CLDN18 and CLDN10), cytokine–cytokine receptor interaction, and hematopoietic cell lineage (involved CSF1 and IL9R) were identified. Conclusion The identified differentially expressed miRNAs and mRNAs may be involved in the pathology of osteonecrosis of the femoral head.

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RCANs regulate the convergent roles of NFATc1 in bone homeostasis

Cited by 16 publications

References 38 publications

C-phycocyanin attenuates RANKL-induced osteoclastogenesis and bone resorption in vitro through inhibiting ROS levels, NFATc1 and NF-κB activation

C-phycocyanin attenuates RANKL-induced osteoclastogenesis and bone resorption in vitro through inhibiting ROS levels, NFATc1 and NF-κB activation

Expression and function of the P2X7 receptor in human osteoblasts: The role of NFATc1 transcription factor

Identifying the Potential Differentially Expressed miRNAs and mRNAs in Osteonecrosis of the Femoral Head Based on Integrated Analysis

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