Direct actions of leptin on bone remodeling.

Abstract

From the time of its original description almost a decade ago [1] leptin was regarded as a hormone originating in the adipocyte whose primary target was within the central nervous system. There, it regulates appetite and reproductive function. It has now become clear that leptin receptors are much more widely distributed than just the hypothalamus, and the skeleton has emerged as an important site of action of leptin. This is suggested by the demonstration of the signalling form of the leptin receptor in human osteoblasts [2–4], rat osteoblasts [5, 6], human chondrocytes [6], porcine chondrocytes [2], human mesenchymal stem cells undergoing osteogenic differentiation [7], and in osteoblastic and chondrocytic cell lines [5, 8]. Consistent with this receptor data, there is now abundant evidence indicating that leptin directly promotes the differentiation and growth of cells of the osteoblast lineage. Thomas et al. [9] found that leptin promoted differentiation of a human marrow stromal cell line into an osteoblast phenotype, and that it increased synthesis of bone matrix proteins, such as type I collagen and osteocalcin, in these cells. Similar findings have been reported by Gordeladze et al. [10] in studies of primary human osteoblasts, in which they also found that leptin reduced apoptosis and increased formation of mineralized bone nodules. Iwaniec et al. [11] have reported increased numbers of mineralized bone nodules in primary osteoblast cultures, and Reseland et al. [12] demonstrated this with both primary human osteoblast cultures and in osteosarcoma cell lines. We have found that low concentrations of leptin (>10 M) increase proliferation of isolated fetal rat osteoblasts to an extent comparable to that of IGF1 [6]. Thus, there is agreement across a range of in vitro models that leptin is anabolic to osteoblasts. There is also evidence that leptin directly regulates osteoclast development. Holloway et al. [13] have shown that leptin inhibits osteoclast generation from human peripheral blood mononuclear cells by reducing production of RANK in mononuclear cells. These findings are complemented by the report of Burguera et al. [14] that leptin increases osteoprotegerin levels and decreases RANK-ligand levels in human marrow stromal cells. Leptin (‡10 M) also inhibits osteoclastogenesis in mouse bone marrow cultures [6]. The effects of leptin on osteoclasts could be contributed to by its stimulation of the secretion of interleukin-1 receptor antagonist from monocytic and lymphocytic cells, which will reduce osteoclast recruitment [15, 16]. These in vitro findings of leptin effects on osteoclasts explain the clinical observations of an inverse relationship between serum leptin concentrations and bone resorption markers in human fetuses [17] and in postmenopausal women [18]. Thus, there is a consistent body of evidence suggesting that leptin will impact positively on bone density as a result of its dual effects on bone formation and resorption. Leptin may also impact on skeletal size since it acts on chondrocytes. We have demonstrated the presence of the leptin receptor in chondrocytes from human articular cartilage, and that proliferation of ovine and canine chondrocytes is promoted by leptin [6]. Systemic administration of leptin to adult mice increases the thickness of their growth plates [6]. Maor et al. [19] have shown specific binding sites for leptin in the chondrocyte cell population of skeletal growth centers in the mouse mandibular condyle. Leptin stimulated cell proliferation and increased the width of the chondroprogenitor zone in this model. These findings are reflected in the reduced femoral length of both the leptin-deficient mouse (Fig. 1) [2] and the leptin-resistant rat [20]. The positive effect of leptin on skeletal size suggests that this hormone may be a contributor to the increases in stature of successive generations of humans that has been observed over the last century or more [21]. As nutrition has improved, leptin concentrations may have increased with a consequent increase in growth and adult height. The final integration of the direct effects of leptin on bone cells seen in vitro occurs in at least three different ways. One is in human studies of the relationships between leptin and bone density. Circulating leptin conCorrespondence to: I. R. Reid; E-mail: i.reid@auckland.ac.nz Calcif Tissue Int (2004) 74:313–316 DOI: 10.1007/s00223-002-0015-z Calcified Tissue International