Abstract
Longitudinal bone growth ceases with growth plate senescence during puberty. However, the molecular mechanisms of this phenomenon are largely unexplored. Here, we examined Wnt-responsive genes before and after growth plate senescence and found that CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway, was gradually elevated with reduction of Wnt/β-catenin signaling during senescent changes of rodent growth plate. Cxxc5 -/- mice demonstrated delayed growth plate senescence and tibial elongation. As CXXC5 functions by interacting with dishevelled (DVL), we sought to identify small molecules capable of disrupting this interaction. In vitro screening assay monitoring CXXC5-DVL interaction revealed that several indirubin analogs were effective antagonists of this interaction. A functionally improved indirubin derivative, KY19382, elongated tibial length through delayed senescence and further activation of the growth plate in adolescent mice. Collectively, our findings reveal an important role for CXXC5 as a suppressor of longitudinal bone growth involving growth plate activity.
Highlights
Longitudinal bone growth takes place in the growth plate, which is composed of a thin layer of transient cartilage tissue
The mRNA level of Cxxc5, a negative regulator of Wnt/β-catenin signaling, was gradually elevated during pubertal progression (GEO: GSE16981) (Fig 1B), showing a statistically significant increase at 12 wk compared to other inhibitors of Wnt/ β-catenin signaling (Apcdd1, Cxxc4, Dkk2, Igfbp4, Sfrp family, Shisa family, Sost, and Wif1) (Fig S1)
Up-regulation of Cxxc5 were confirmed by quantitative real-time PCR analyses at the later stages of pubertal progression compared to 3-wk-old mice (Fig 1C)
Summary
Longitudinal bone growth takes place in the growth plate, which is composed of a thin layer of transient cartilage tissue. Chondrocytes in this cartilage layer proliferate and undergo hypertrophic differentiation followed by apoptosis and subsequent remodeling into bone tissue, resulting in bone elongation (Kronenberg, 2003). Many children undergo early pubertal development with growth plate senescence occurring sooner. These phenomena, known as precocious puberty, reveal premature termination of longitudinal bone growth, resulting in short adult stature (Carel et al, 2004). The underlying mechanisms that regulate growth plate senescence are largely unknown
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