Thyroid hormone actions on cartilage and bone: interactions with other hormones at the epiphyseal plate and effects on linear growth.

Normal linear growth is determined by variable contributions from genetic, nutritional and endocrine factors and continues until bone maturation and epiphyseal closure in early adulthood. The major systemic hormones that influence growth during childhood include thyroid hormone (T3), growth hormone (GH), insulin-like growth factors (IGF) and glucocorticoids, whereas an increasing contribution from sex steroids develops during adolescence (Underwood & Van Wyk 1992, Weiss & Refetoff 1996). Recently, two signalling proteins, Indian hedgehog (Ihh) and parathyroid hormone-related peptide (PTHrP), have also been found to be crucial for the co-ordinated regulation of the pace of growth plate chondrocyte differentiation (Lanske et al. 1996, Vortkamp et al. 1996, Wallis 1996). These molecules form an integrated negative feedback loop that regulates the rate of endochondral ossification. However, it is not known how systemic hormones and other local factors that act on the growth plate may regulate expression of Ihh and PTHrP or influence activity of the feedback loop to alter the rate of chondrocyte differentiation during growth. In this review, we focus on the actions of T3 and its interactions with other hormone signalling pathways in the control of growth. The field highlights a poorly studied area that has important applications to understanding skeletal development and the regulation of linear growth. There are large gaps in our knowledge concerning the actions of T3 in bone and cartilage, and fundamental questions have yet to be answered. For example, a current point of controversy is whether the major skeletal effects of T3 result from its direct effects on the skeleton or via interactions with GH and IGF-1. Recent evidence documenting the expression of T3 receptors in osteoblasts and chondrocytes indicates that direct T3 effects on the skeleton are likely to be important. Despite this, the target genes that are directly responsive to T3 in bone cells have not been identified. Furthermore, the precise localisation of T3-responsive cells within the growth plate and skeleton and the ontogeny of T3 receptors in developing cartilage and bone are unknown. Thus it is not clear whether T3 acts directly and independently on both osteoblasts and osteoclasts, in addition to chondrocytes, or whether the effects of thyroid hormones on bone turnover and growth are mediated primarily by one cell lineage and subsequently by other secondary events. The aim of this review is to summarise the effects of T3 on bone and growth plate cartilage and to discuss the interactions between T3 and other hormones and their possible relationship to the fundamentally important Ihh/ PTHrP feedback loop. The roles of other important growth factors and cytokines are beyond the scope of this review. In a discussion of this type, it is important to be aware that much of our knowledge is derived from studies using a variety of animal species, including rodents, cattle, pigs, rabbits and birds, in addition to humans. Thus data can be conflicting, as there are basic differences between species in the growth plate ossification process and in vitro models may not reflect the intact organism. For example, rodent growth plates fuse in late adulthood, whereas this occurs towards the end of adolescence in man. In birds, the system may differ further, as the avian growth plate is more fibrous than its mammalian counterpart. Despite these reservations, there are fundamental similarites in endochondral ossification across species that do allow cautious but valid interpretation of the available data.