Fibroblast growth factor receptor 3 effects on proliferation and telomerase activity in sheep growth plate chondrocytes

Logan B Smith,Janelle M Belanger,Anita M Oberbauer

doi:10.1186/2049-1891-3-39

Logan B Smith, Janelle M Belanger + Show 1 more

Open Access

https://doi.org/10.1186/2049-1891-3-39

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Abstract

BackgroundFibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Thyroid hormone (T3) plays a role in cellular maturation of growth plate chondrocytes and a known target of T3 is FGFR3. The present study addressed whether reduced FGFR3 expression enhanced telomerase activity, mRNA expression of telomerase reverse transcriptase (TERT) and RNA component of telomerase (TR), and chondrocyte proliferation, and whether the stimulation of FGFR3 by T3 evoked the opposite response.ResultsSheep growth-plate proliferative zone chondrocytes were cultured and transfected with siRNA to reduce FGFR3 expression; FGFR3 siRNA reduced chondrocyte FGFR3 mRNA and protein resulting in greater proliferation and increased TERT mRNA expression and telomerase activity (p < 0.05). Chondrocytes treated with T3 significantly enhanced FGFR3 mRNA and protein expression and reduced telomerase activity (p < 0.05); TERT and TR were not significantly reduced. The action of T3 at the growth plate may be partially mediated through the FGFR3 pathway.ConclusionsThe results suggest that FGFR3 inhibits chondrocyte proliferation by down-regulating TERT expression and reducing telomerase activity indicating an important role for telomerase in sustaining chondrocyte proliferative capacity during bone elongation.

Highlights

Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation
FGFR3 Small interfering RNA (siRNA) Untransfected baseline control chondrocytes were not significantly different from scrambled double stranded RNA (dsRNA) (ScR) control treated chondrocytes, or chondrocytes treated with vehicle controls, for the Deoxyribonucleic acid (DNA), Messenger Ribonucleic acid (RNA) (mRNA), or protein quantity evaluated at all post transfection days sampled (p > 0.2, data not shown)
The present study demonstrated that reduced FGFR3 expression confers increased proliferative capacity on growth plate chondrocytes through enhanced telomerase reverse transcriptase (TERT) levels in vitro and suggests a likely translation to enhanced overall bone length in vivo

Summary

Introduction

Fibroblast growth factor receptor 3 (FGFR3) inhibits growth-plate chondrocyte proliferation and limits bone elongation. Gain-of-function FGFR3 mutations cause dwarfism, reduced telomerase activity and shorter telomeres in growth plate chondroyctes suggesting that FGFR3 reduces proliferative capacity, inhibits telomerase, and enhances senescence. Linear bone growth is a function of the proliferative capacity of the endochondral growth plate and the size of the hypertrophic cells. Fibroblast growth factor receptor 3 (FGFR3) is a critical regulator of growth plate chondrocyte function through its inhibition of proliferation [3,4]. Gain-of-function mutations in FGFR3 cause severe restriction of skeletal growth resulting in dwarfism in both mice and humans [5]. The inhibitory regulation by FGFR3 and its localized expression within the growth plate proliferative zone are unique among the family of four fibroblast growth factor receptors. Evidence suggests that FGFR1 may promote differentiation in the hypertrophic growth plate zone following exit from the proliferative zone [8,9]

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