PMID- 34228377
OWN - NLM
STAT- MEDLINE
DCOM- 20220217
LR  - 20221003
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Print)
IS  - 0730-2312 (Linking)
VI  - 122
IP  - 10
DP  - 2021 Oct
TI  - Inhibition of NFAM1 suppresses phospho-SAPK/JNK signaling during osteoclast 
      differentiation and bone resorption.
PG  - 1534-1543
LID - 10.1002/jcb.30076 [doi]
AB  - We have recently demonstrated NFAT activating protein with ITAM motif 1 (NFAM1) 
      signaling increases osteoclast (OCL) formation/bone resorption associated with 
      the Paget's disease of bone, however, the underlying molecular mechanisms of the 
      NFAM1 regulation of OCL differentiation and bone resorption remains unclear. 
      Here, we showed that RANK ligand stimulation enhances NFAM1 expression in 
      preosteoclast cells. Conditioned media collected from RANKL stimulated RAW264.7 
      NFAM1 knockdown (KD) stable cells showed inhibition of interleukin-6 (2.5-fold), 
      tumour necrosis factor-alpha (2.2-fold) and CXCL-5 (3-fold) levels compared to 
      wild-type (WT) cells. Further, RANKL stimulation significantly increased p-STAT6 
      expression (5.5-fold) in WT cells, but no significant effect was observed in 
      NFAM1-KD cells. However, no changes were detected in signal transducer and 
      activator of transcription 3 levels in either of cell groups. Interestingly, 
      NFAM1-KD suppressed the RANKL stimulated c-fos, p-c-Jun and c-Jun N-terminal 
      kinase (JNK) activity in preosteoclasts. We further showed that the suppression 
      of JNK activity is through inhibition of p-SAPK/JNK in these cells. In addition, 
      NFATc1 expression, a critical transcription factor associated with 
      osteoclastogenesis is significantly inhibited in NFAM1-KD preosteoclast cells. 
      Interestingly, NFAM1 inhibition suppressed the OCL differentiation and bone 
      resorption capacity in mouse bone marrow cell cultures. We also demonstrated 
      inhibition of tartrate-resistant acid phosphatase expression in RANKL stimulated 
      NFAM1-KD preosteoclast cells. Thus, our results suggest that NFAM1 control 
      SAPK/JNK signaling to modulate osteoclast differentiation and bone resorption.
CI  - (c) 2021 Wiley Periodicals LLC.
FAU - Ethiraj, Purushoth
AU  - Ethiraj P
AUID- ORCID: 0000-0002-0679-6041
AD  - Department of Pediatrics, Darby Children's Research Institute, Charleston, South 
      Carolina, USA.
FAU - Haque, Ishraq A
AU  - Haque IA
AD  - Department of Pediatrics, Darby Children's Research Institute, Charleston, South 
      Carolina, USA.
FAU - Alford, Anna K
AU  - Alford AK
AD  - Department of Pediatrics, Darby Children's Research Institute, Charleston, South 
      Carolina, USA.
FAU - Gou, Wenyu
AU  - Gou W
AD  - Department of Surgery, College of Dental Medicine, Medical University of South 
      Carolina, Charleston, South Carolina, USA.
FAU - Singh, Toolika
AU  - Singh T
AD  - Department of Cardiology, College of Dental Medicine, Medical University of South 
      Carolina, Charleston, South Carolina, USA.
FAU - Sambandam, Yuvaraj
AU  - Sambandam Y
AD  - Department of Surgery, Feinberg School of Medicine, Northwestern University, 
      Chicago, Illinois, USA.
FAU - Hathaway-Schrader, Jessica D
AU  - Hathaway-Schrader JD
AD  - Department of Oral Health Sciences, College of Dental Medicine, Medical 
      University of South Carolina, Charleston, South Carolina, USA.
FAU - Reddy, Sakamuri V
AU  - Reddy SV
AD  - Department of Pediatrics, Darby Children's Research Institute, Charleston, South 
      Carolina, USA.
LA  - eng
GR  - C06 RR015455/RR/NCRR NIH HHS/United States
GR  - R56 AG052511/AG/NIA NIH HHS/United States
GR  - T32 DE017551/DE/NIDCR NIH HHS/United States
GR  - 1R56AG052511-01/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210706
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Membrane Proteins)
RN  - 0 (NFATC Transcription Factors)
RN  - 0 (Nfam1 protein, mouse)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 8)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 4)
SB  - IM
MH  - Animals
MH  - Bone Resorption/metabolism/*pathology
MH  - Cell Differentiation/physiology
MH  - Gene Expression Regulation
MH  - MAP Kinase Kinase 4/*antagonists & inhibitors/genetics/metabolism
MH  - Membrane Proteins/*antagonists & inhibitors/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mitogen-Activated Protein Kinase 8/*antagonists & inhibitors/genetics/metabolism
MH  - NFATC Transcription Factors/genetics/metabolism
MH  - Osteoclasts/*cytology/metabolism
MH  - *Osteogenesis
MH  - Phosphorylation
PMC - PMC8479865
MID - NIHMS1719362
OTO - NOTNLM
OT  - JNK activity
OT  - NFAM1
OT  - NFATc1
OT  - Osteoclast
OT  - c-fos
OT  - p-SAPK/JNK
COIS- CONFLICT OF INTEREST The authors declare no conflict of interests.
EDAT- 2021/07/07 06:00
MHDA- 2022/02/19 06:00
PMCR- 2022/10/01
CRDT- 2021/07/06 13:28
PHST- 2021/04/27 00:00 [revised]
PHST- 2019/12/03 00:00 [received]
PHST- 2021/06/13 00:00 [accepted]
PHST- 2021/07/07 06:00 [pubmed]
PHST- 2022/02/19 06:00 [medline]
PHST- 2021/07/06 13:28 [entrez]
PHST- 2022/10/01 00:00 [pmc-release]
AID - 10.1002/jcb.30076 [doi]
PST - ppublish
SO  - J Cell Biochem. 2021 Oct;122(10):1534-1543. doi: 10.1002/jcb.30076. Epub 2021 Jul 
      6.