Effects of growth hormone and insulin‐like growth factors on human osteoblasts

Clinical studies as well as animal studies have demonstrated that growth hormone (GH) is important for normal bone remodelling. Patients with GH deficiency have decreased bone mineral density that is reversed by long-term treatment with GH [1]. The mechanism(s) of this effect is not fully understood. It could be either regulation of bone resorption, regulation of bone formation or both. Insulin-like growth factors (IGFs) are also believed to be of importance to normal bone physiology, their predominant effect thought to be stimulation of bone formation [2]. IGF-II is expressed in both rodent and human osteoblasts. IGF-I is produced by rodent [3–5] osteoblasts, whereas contradictory results have been presented for human osteoblasts. Chenu and colleagues [6], but not Kassem et al. [7], were able to detect significant amounts of IGF-I in the culture medium from human osteoblast-like (hOB) cells. Studies both detecting [8–10] and not detecting [11] IGF-I mRNA transcripts in human osteoblasts have been presented. However, an in situ hybridization study demonstrated that osteoblasts in adult human osteophyte tissue express the IGF-I mRNA transcript [12]. Human osteoblasts express functional GH and IGF-I receptors, indicating that GH and IGF-I can stimulate bone formation via a direct stimulation of osteoblasts [13]. In a study by Langdahl et al. [14] in this issue of the European Journal of Clinical Investigation it is demonstrated that the effects of GH and IGFs are dependent on the stage of differentiation of the human osteoblasts. Thus, the effects of GH and IGFs on immature human bone marrow stromal cells were different from the effects on more mature human osteoblasts. This finding indicates that the expression of GH receptors and IGF-I receptors is dependent on the stage of differentiation of the osteoblasts. Recent in vivo results are supportive of the notion that at least some of the GH effects on bone remodelling are mediated via liver-produced or locally produced IGF-I. Local administration of GH, but not IGF-I, stimulates the local production of IGF-I by stimulating the transcription from the IGF-I gene [1], giving direct experimental support for the notion that there is an interplay between GH and IGF-I. To determine the importance of IGF-I as a mediator of GH action, endogenous IGF-I was sequestered by an antiserum to IGF in bone cell cultures. As a result, the proliferative action of GH was abolished [15], indicating that local IGF-I is important for the GH-induced cell proliferation. In summary, GH induces IGF-I expression in rodent osteoblasts, although the induction of IGF-I by GH in human osteoblasts is uncertain. A widely discussed question during the last two decades has been whether GH acts on tissues directly, or whether the effect is mediated by a liver-derived growth factor, initially called sulphation factor but later renamed somatomedin and subsequently shown to be identical to insulinlike growth factor I (IGF-I). According to the original somatomedin hypothesis, GH stimulates skeletal growth by stimulating liver production of somatomedin, which, in turn, stimulates longitudinal bone growth in an endocrine manner [16]. In the early 1980s, the somatomedin hypothesis was challenged by a study demonstrating that injection of GH directly into the rat tibial growth plate stimulates longitudinal bone growth at the site of injection [17]. This initial observation has subsequently been confirmed and extended, and it is now well documented that GH stimulates the growth of many different tissues directly. By studying the effects of GH and IGF-I in 3T3 preadipocytes, Green and colleagues [18] made the observation that GH and IGF-I act on cells at different stages of maturation. Thus, GH was found to stimulate young preadipocytes, whereas IGF-I stimulated cells at a later stage of development [18]. The hypothesis postulated by Green and colleagues [18] that GH acts on progenitor cells and that IGFI stimulates the subsequent clonal expansion was named the ‘dual-effector theory’. The finding that GH stimulates