Nfatc1 Is a Functional Transcriptional Factor Mediating Nell-1-Induced Runx3 Upregulation in Chondrocytes

Chenshuang Li; Zhong Zheng; Xinli Zhang; Greg Asatrian; Eric Chen; Richard Song; Cymbeline Culiat; Kang Ting; Chia Soo

doi:10.3390/ijms19010168

Nfatc1 Is a Functional Transcriptional Factor Mediating Nell-1-Induced Runx3 Upregulation in Chondrocytes

Int J Mol Sci. 2018 Jan 6;19(1):168. doi: 10.3390/ijms19010168.

Authors

Chenshuang Li¹, Zhong Zheng², Xinli Zhang³, Greg Asatrian⁴, Eric Chen⁵, Richard Song⁶, Cymbeline Culiat⁷, Kang Ting⁸, Chia Soo⁹

Affiliations

¹ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].
² Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].
³ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].
⁴ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].
⁵ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].
⁶ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].
⁷ NellOne Therapeutics, Inc., 99 Midway Ln # E, Oak Ridge, TN 37830, USA. [email protected].
⁸ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].
⁹ Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery, the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA. [email protected].

Abstract

Neural EGFL like 1 (Nell-1) is essential for chondrogenic differentiation, maturation, and regeneration. Our previous studies have demonstrated that Nell-1's pro-chondrogenic activities are predominantly reliant upon runt-related transcription factor 3 (Runx3)-mediated Indian hedgehog (Ihh) signaling. Here, we identify the nuclear factor of activated T-cells 1 (Nfatc1) as the key transcriptional factor mediating the Nell-1 → Runx3 signal transduction in chondrocytes. Using chromatin immunoprecipitation assay, we were able to determine that Nfatc1 binds to the -833--810 region of the Runx3-promoter in response to Nell-1 treatment. By revealing the Nell-1 → Nfatc1 → Runx3 → Ihh cascade, we demonstrate the involvement of Nfatc1, a nuclear factor of activated T-cells, in chondrogenesis, while providing innovative insights into developing a novel therapeutic strategy for cartilage regeneration and other chondrogenesis-related conditions.

Keywords: chondrogenesis; neural EGFL like 1 (Nell-1); nuclear factor of activated T-cells 1 (Nfatc1); runt-related transcription factor 3 (Runx3).

MeSH terms

Adipose Tissue / cytology
Animals
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism
Calcium-Binding Proteins / pharmacology*
Cell Differentiation / drug effects
Cells, Cultured
Chondrocytes / cytology
Chondrocytes / metabolism
Chondrogenesis / drug effects
Core Binding Factor Alpha 1 Subunit / deficiency
Core Binding Factor Alpha 1 Subunit / genetics
Core Binding Factor Alpha 2 Subunit / antagonists & inhibitors
Core Binding Factor Alpha 2 Subunit / genetics
Core Binding Factor Alpha 2 Subunit / metabolism
Core Binding Factor Alpha 3 Subunit / genetics
Core Binding Factor Alpha 3 Subunit / metabolism*
Glycoproteins / genetics
Glycoproteins / metabolism
Glycoproteins / pharmacology*
Mice
Mice, Knockout
NFATC Transcription Factors / antagonists & inhibitors
NFATC Transcription Factors / genetics
NFATC Transcription Factors / metabolism*
Promoter Regions, Genetic
Protein Binding
RNA Interference
RNA, Small Interfering / metabolism
Signal Transduction / drug effects
Up-Regulation / drug effects*

Substances

Calcium-Binding Proteins
Core Binding Factor Alpha 1 Subunit
Core Binding Factor Alpha 2 Subunit
Core Binding Factor Alpha 3 Subunit
Glycoproteins
NFATC Transcription Factors
Nell1 protein, mouse
RNA, Small Interfering
Runx1 protein, mouse
Runx2 protein, mouse
Runx3 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding