Neural EGFL like 1 as a potential pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug

Chenshuang Li; Zhong Zheng; Pin Ha; Wenlu Jiang; Emily A Berthiaume; Seungjun Lee; Zane Mills; Hsinchuan Pan; Eric C Chen; Jie Jiang; Cymbeline T Culiat; Xinli Zhang; Kang Ting; Chia Soo

doi:10.1016/j.biomaterials.2019.119541

Neural EGFL like 1 as a potential pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug

Biomaterials. 2020 Jan:226:119541. doi: 10.1016/j.biomaterials.2019.119541. Epub 2019 Oct 12.

Authors

Chenshuang Li¹, Zhong Zheng², Pin Ha³, Wenlu Jiang⁴, Emily A Berthiaume⁵, Seungjun Lee⁶, Zane Mills⁷, Hsinchuan Pan⁸, Eric C Chen⁹, Jie Jiang¹⁰, Cymbeline T Culiat¹¹, Xinli Zhang¹², Kang Ting¹³, Chia Soo¹⁴

Affiliations

¹ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: chenshuanglee@gmail.com.
² Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: zzheng@dentistry.ucla.edu.
³ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: hapin1987@ucla.edu.
⁴ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: wlulujiang@outlook.com.
⁵ David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: EBerthiaume@mednet.ucla.edu.
⁶ Department of Chemistry and Biochemistry, School of Letters and Science, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: seung7902@ucla.edu.
⁷ Department of Ecology and Evolutionary Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: zane.mills4823@gmail.com.
⁸ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: leinadp@gmail.com.
⁹ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: ericchenucla@g.ucla.edu.
¹⁰ Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: jie.jiang@som.umaryland.edu.
¹¹ NellOne Therapeutics, Inc., Oak Ridge, TN, 37830, USA. Electronic address: cymbeline@nell-one.com.
¹² Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: xinli@ucla.edu.
¹³ Division of Growth and Development, Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: kting@dentistry.ucla.edu.
¹⁴ Division of Plastic and Reconstructive Surgery and Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA. Electronic address: bsoo@ucla.edu.

Abstract

Arthritis, an inflammatory condition that causes pain and cartilage destruction in joints, affects over 54.4 million people in the US alone. Here, for the first time, we demonstrated the emerging role of neural EGFL like 1 (NELL-1) in arthritis pathogenesis by showing that Nell-1-haploinsufficient (Nell-1^+/6R) mice had accelerated and aggravated osteoarthritis (OA) progression with elevated inflammatory markers in both spontaneous primary OA and chemical-induced secondary OA models. In the chemical-induced OA model, intra-articular injection of interleukin (IL)1β induced more severe inflammation and cartilage degradation in the knee joints of Nell-1^+/6R mice than in wildtype animals. Mechanistically, in addition to its pro-chondrogenic potency, NELL-1 also effectively suppressed the expression of inflammatory cytokines and their downstream cartilage catabolic enzymes by upregulating runt-related transcription factor (RUNX)1 in mouse and human articular cartilage chondrocytes. Notably, NELL-1 significantly reduced IL1β-stimulated inflammation and damage to articular cartilage in vivo. In particular, NELL-1 administration markedly reduced the symptoms of antalgic gait observed in IL1β-challenged Nell-1^+/6R mice. Therefore, NELL-1 is a promising pro-chondrogenic, anti-inflammatory dual-functional disease-modifying osteoarthritis drug (DMOAD) candidate for preventing and suppressing arthritis-related cartilage damage.

Keywords: Cartilage damage; Disease-modifying osteoarthritis drug (DMOAD); Inflammation; Neural EGFL like 1 (NELL-1); Osteoarthritis; Runt-related transcription factor 1 (RUNX1).

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Anti-Inflammatory Agents / pharmacology
Anti-Inflammatory Agents / therapeutic use
Calcium-Binding Proteins / genetics*
Cartilage, Articular*
Chondrocytes
Chondrogenesis
Interleukin-1beta / pharmacology
Mice
Osteoarthritis* / drug therapy
Pharmaceutical Preparations*

Substances

Anti-Inflammatory Agents
Calcium-Binding Proteins
Interleukin-1beta
Nell1 protein, mouse
Pharmaceutical Preparations

Abstract

Publication types

MeSH terms

Substances

Grants and funding