Combining exercise and growth hormone therapy: how can we translate from animal models to chronic kidney disease children?

Renal osteodystrophy (ROD) and growth retardation are frequent complications of paediatric chronic kidney disease (CKD) secondary to an association of abnormalities including impaired growth hormone (GH) metabolism, hypoor hyperparathyroidism, vitaminD deficiency, malnutrition, hypogonadism and drug toxicity [1]. The impact of CKD-associated bone and mineral disorders (CKD-MBDs) can be a short-term issue (abnormal mineral metabolism), but also a long-term one (ROD, fractures, impaired growth, vascular calcifications and mortality) [1]. These complications affect the quality of life because of their consequences on mental and physical wellbeing, but they also strongly impair mineral metabolism and bone quality and ultimately cause cardiovascular disease, which is the major cause of death in paediatric CKD [1]. Linear growth is specific to paediatric patients: it is a highly regulated process occurring through the modelling of new bone by skeletal accretion and longitudinal growth at the growth plate. Chondrocytes are a cornerstone of this process, along with GH [2]. One-third of the total growth occurs during infancy (i.e. the first 2 years of life), depending mainly on nutritional parameters [2]. Later childhood is marked by a constant growth velocity (but of lesser intensity than in the early stages); this phenomenon is driven by GH and thyroid hormone.When puberty occurs, testosterone and oestrogen further increase growth velocity. The epiphyseal cartilage goes through a process of progressive maturation during infancy, childhood and adolescence. When no additional epiphyseal cartilage remains to allow further growth of long bones, fusion occurs between the shaft and the epiphysis, ending the linear growth process. In children, bone formation occurs by to two different mechanisms: the first mechanism is endochondral ossification (i.e. modelling of new bone by longitudinal growth and skeletal accretion from the growth plate by chondrocytes), while the second one is similar to that observed in adults, corresponding to the skeletal remodelling of existing mineralized bone tissue by osteoblasts and osteoclasts [3]. The growth plate is an avascular tissue located between the metaphyses and epiphyses in long bones; endochondral bone formation corresponds to its progressive replacement by bone. Its regulation corresponds to a complex cascade of nutritional, cellular, paracrine and endocrine factors [4]. The growth plate consists of three different zones: resting, proliferative and hypertrophic, with each zone containing chondrocytes at different stages of differentiation, i.e. small chondrocytes with low replication rates, flat chondrocytes with high replication rates and chondrocytes at the later stage of differentiation, respectively [5]. The cellular factors involved in endochondral ossification include apoptosis, autophagy, hypoxia and trans-differentiation [5]. In terms of paracrine factors involved in the proliferation and differentiation of chondrocytes, the PTH/PTH-related proteinreceptor axis, the IndianHedgehog pathway and the Runx2 transcription factors are key components of the cascade, along with fibroblast growth factor receptor and bone morphogenetic protein signalling [5]. GH and insulin-like growth factor-1 (IGF-1) are obviously themost important endocrine factors involved, but oestrogens and androgens also play a role [5]. GH exerts at least four main actions on the growth plate: (i) increased local synthesis of IGF-1 for a paracrine effect (i.e. clonal expansion of proliferating chondrocytes), (ii) a stimulating effect on cellular differentiation to convert chondrocytes into osteogenic cells, (iii) increased cellular proliferation rate and (iv) increased synthesis and deposition of proteins by chondrocytic and osteogenic