Role of thyroid hormone receptor-α1 in endochondral ossification.

Abstract

Thyroid hormones are important regulators of postnatal skeletal development, linear growth, and bone maintenance. Thyroid hormone deficiency during childhood results in growth retardation and delayed bone age and tooth eruption, with epiphyseal dysgenesis and linear growth arrest evident in severe cases (1). Treatment of hypothyroid children with T4 results in rapid catch-up of bone age and growth, although short stature may persist in individuals who have prolonged hormone deficiency prior to treatment (2, 3). In contrast, thyrotoxicosis induces premature bone maturation and increases linear growth velocity, although the early closure of the growth plates and premature fusion of the sutures of the skull can lead to persistent short stature and craniosynostosis in children with severe or undiagnosed and continuing hyperthyroidism (4). Overall, these observations reveal exquisite sensitivity of the postnatal skeleton to thyroid hormones and the requirement for euthyroid status to ensure normal bone development and growth. Endochondral ossification is the mechanism underlying bone formation on a cartilage scaffold and the process by which linear growth proceeds in the epiphyseal growth plates (5). Mesenchyme progenitor cells condense and differentiate into chondrocytes, which proliferate and secrete matrix proteins to form a cartilage template for bone formation. At the primary ossification center a tightly regulated program of chondrocyte organization, proliferation, hypertrophic differentiation, and apoptosis results in cartilage mineralization. Vascular invasion and migration of osteoblasts leads to the replacement of mineralized cartilage with trabecular bone. In addition, mesenchyme progenitors condense within perichondrial regions surrounding cartilage and differentiate into osteoblasts, which, via intramembranous ossification, directly form a collar of cortical bone (5). Subsequently, secondary ossification centers form at the ends of long bones, but they remain separated from the primary ossification center by the epiphyseal growth plates. An organized program of chondrocyte proliferation, hypertrophy, and apoptosis continues in the growth plates. Endochondral ossification thus mediates longitudinal growth until adulthood when the epiphyses fuse and linear growth ceases (5). All of these developmental processes resulting in the formation of primary and secondary ossification centers, establishment of a mineralized cortical bone collar, and the progression of linear growth are sensitive to thyroid hormones (1, 6, 7). The principal actions of thyroid hormones are mediated by nuclear receptors (TR 1, TR 1, or TR 2), which are expressed in tissue-specific patterns and functionasT3-inducible transcription factors (8).Analysis of mouse mutants with disrupted T3 signaling has revealed that TR 1 is the functionally predominant TR isoform expressed in cartilage and bone (1, 6), and the recent identification of patients with autosomal dominant mutations affecting THRA has confirmed the physiological importance and predominance of TR 1 in human skeletal development and postnatal growth (9–12). Nevertheless, and despite considerable advances in recent years, the cell-specific mechanisms and downstream signaling pathways that mediate the developmental effects of thyroid hormones in cartilage and bone remain incompletely understood. Importantly, the widespread endocrine effects of T3 have made it difficult to disentangle local cell-specific T3 actions in cartilage and bone from indirect systemic effects that result from skeletal responses to T3inducible cytokines or growth factors produced in other