A novel prostaglandin E receptor 4 (EP4) small molecule antagonist induces articular cartilage regeneration

Xin Wang,Qianqian Liu,Ning Wang,Mingyao Liu,Peng Chen,Jian Luo,Karan M Shah ,Wenhao Jiang,Yuanjin Zhang,Fanhua Wang,Weiqiang Lü ,Tao Zhong ,Yunyun Jin,Alison Gartland,Hankun Zhang,Zhao Song ,Peng Li,Xu Cao,Xinran Ma,Lei Yang

doi:10.1038/s41421-022-00382-6

Abstract

Articular cartilage repair and regeneration is an unmet clinical need because of the poor self-regeneration capacity of the tissue. In this study, we found that the expression of prostaglandin E receptor 4 (PTGER4 or EP4) was largely increased in the injured articular cartilage in both humans and mice. In microfracture (MF) surgery-induced cartilage defect (CD) and destabilization of the medial meniscus (DMM) surgery-induced CD mouse models, cartilage-specific deletion of EP4 remarkably promoted tissue regeneration by enhancing chondrogenesis and cartilage anabolism, and suppressing cartilage catabolism and hypertrophy. Importantly, knocking out EP4 in cartilage enhanced stable mature articular cartilage formation instead of fibrocartilage, and reduced joint pain. In addition, we identified a novel selective EP4 antagonist HL-43 for promoting chondrocyte differentiation and anabolism with low toxicity and desirable bioavailability. HL-43 enhanced cartilage anabolism, suppressed catabolism, prevented fibrocartilage formation, and reduced joint pain in multiple pre-clinical animal models including the MF surgery-induced CD rat model, the DMM surgery-induced CD mouse model, and an aging-induced CD mouse model. Furthermore, HL-43 promoted chondrocyte differentiation and extracellular matrix (ECM) generation, and inhibited matrix degradation in human articular cartilage explants. At the molecular level, we found that HL-43/EP4 regulated cartilage anabolism through the cAMP/PKA/CREB/Sox9 signaling. Together, our findings demonstrate that EP4 can act as a promising therapeutic target for cartilage regeneration and the novel EP4 antagonist HL-43 has the clinical potential to be used for cartilage repair and regeneration.

Highlights

Mechanical loading, inflammation, trauma, acute physical injury, and aging are some of the causes for cartilage defects (CDs), and the limited self-healing ability of the articular cartilage leads to production of collagen type I (Col1) and fibrocartilage instead of the stable mature cartilage[1,2]
Remarkable upregulation of EP4 was observed in the injured cartilage compared to the sham operated cartilage in both microfracture (MF) surgery-induced cartilage defect (CD) mouse model and destabilization of the medial meniscus (DMM) surgery-induced CD mouse model (Fig. 1c, d)
Currently, there are no effective therapies for articular cartilage defects, making it an unmet clinical need

Summary

Introduction

Mechanical loading, inflammation, trauma, acute physical injury, and aging are some of the causes for cartilage defects (CDs), and the limited self-healing ability of the articular cartilage leads to production of collagen type I (Col1) and fibrocartilage instead of the stable mature cartilage[1,2]. Limited clinical approaches are available to repair defective cartilage, mainly due to the poor regenerative and reparative capacity of cartilage. The widely used microfracture (MF) surgery was shown to enhance migration of stem cells from bone marrow to the injured cartilage[1,6–8], but only to regenerate fibrocartilage with inferior biochemical and biomechanical characters[1,9]. Jin et al Cell Discovery (2022)8:24 in clinical trials in recent years, but these therapies so far do not contribute to improvement in functional outcomes[1,2,10,11], making cartilage regeneration an urgent unmet clinical need.

Methods

Results

Conclusion