Indirubin-3\u2032-oxime stimulates chondrocyte maturation and longitudinal bone growth via activation of the Wnt/\u03b2-catenin pathway

Sehee Choi,Hyun-Yi Kim,Pu-Hyeon Cha,Kang-Yell Choi

doi:10.1038/s12276-019-0306-3

Sehee Choi, Hyun-Yi Kim + Show 2 more

Open Access

https://doi.org/10.1038/s12276-019-0306-3

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Abstract

Researchers have shown increased interest in determining what stimulates height. Currently, many children undergo precocious puberty, resulting in short stature due to premature closure of the growth plate. However, the current approach for height enhancement is limited to growth hormone treatment, which often results in side effects and clinical failure and is costly. Although recent studies have indicated the importance of paracrine signals in the growth plate for longitudinal bone growth, height-stimulating agents targeting the signaling pathways involved in growth plate maturation remain unavailable in the clinic. The Wnt/β-catenin pathway plays a major role in the maturation of growth plate chondrocytes. In this study, by using an ex vivo tibial culture system, we identified indirubin-3′-oxime (I3O) as a compound capable of enhancing longitudinal bone growth. I3O promoted chondrocyte proliferation and differentiation via activation of the Wnt/β-catenin pathway in vitro. Intraperitoneal injection of I3O in adolescent mice increased growth plate height along with incremental chondrocyte maturation. I3O promoted tibial growth without significant adverse effects on bone thickness and articular cartilage. Therefore, I3O could be a potential therapeutic agent for increasing height in children with growth retardation.

Highlights

Height growth occurs rapidly in childhood and eventually ceases during puberty[1]
Longitudinal bone growth occurs at the growth plate via a multistep process that includes the proliferation and hypertrophic differentiation of chondrocytes followed by ossification
The current strategy for the treatment of short stature is restricted to growth hormone (GH) therapy even though it is only effective on patients with GH deficiency, which constitute a minority of children with growth retardation[18]

Summary

Introduction

Height growth occurs rapidly in childhood and eventually ceases during puberty[1]. approaches promoting height at the period before growth plate closure occurs are important. The current therapies for treating children with short stature include administration of growth hormone (GH) alone or together with a gonadotropin-releasing hormone (GnRH) analog[2]; studies have revealed that the efficacy of these therapies is restricted to a minority with GH deficiency[3]. These treatments can result in harmful side effects, such as hyperinsulinism edema, pseudotumor cerebri, and gynecomastia[4]. Circulating endocrine factors have been demonstrated to exert their effects on growth plate chondrocytes through activation of the local signaling pathway within the growth plate[7,8]

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