Thyroid hormone treatment of cultured chondrocytes mimics in vivo stimulation of collagen X mRNA by increasing BMP 4 expression

Abstract

During endochondral bone formation, chondrocytes undergo terminal differentiation, during which the rate of proliferation decreases, cells become hypertrophic, and the extracellular matrix is altered by production of collagen X, as well as proteins required for matrix mineralization. This maturation process is responsible for most longitudinal bone growth, both during embryonic development and in postnatal long bone growth plates. Among the major signaling molecules implicated in regulation of this process are the positive regulators thyroid hormone (T3) and bone morphogenetic proteins (BMPs). Both T3 and BMPs are essential for endochondral bone formation and cannot compensate for each other, suggesting interaction of the two signaling pathways. We have analyzed the temporal and spatial expression patterns of numerous genes believed to play a role in chondrocyte maturation. Our results show that T3 stimulates collagen X gene expression in cultured chondrocytres with kinetics and magnitude similar to those observed in vivo. Stimulation of collagen X gene expression by T3 occurs only after a significant delay, implying that this hormone may act indirectly. We show further that T3 rapidly stimulates production of BMP 4, concomitant with a decrease in the BMP inhibitor Noggin, potentially resulting in a net increase in BMP signaling. Finally, inhibition of BMP signaling with exogenous Noggin prevents T3 stimulation of collagen X expression, indicating that BMP signaling is essential for this process. These data position thyroid hormone at the top of a T3/BMP cascade, potentially explaining why both pathways are essential for chondrocyte maturation. J. Cell. Physiol. 219: 595-605, 2009. (c) 2009 Wiley-Liss, Inc.

The skeletal consequences of thyrotoxicosis

“…By contrast, childhood hypothyroidism results in growth arrest, delayed bone age and a severe disruption of the growth plate architecture (Rivkees et al 1988, Boersma et al 1996, Huffmeier et al 2007. T 3 excess accelerates the pace of growth plate chondrocyte differentiation via actions on the key Indian hedgehog/ parathyroid hormone-related peptide, bone morphogenetic protein, fibroblast growth factor (FGF), growth hormone (GH), insulin-like growth factor 1 (IGF1) and canonical Wnt signalling pathways , Barnard et al 2005, Dentice et al 2005, O'Shea et al 2005, Lassova et al 2009, Wang et al 2010, Xing et al 2012). In addition, T 3 acts to accelerate cartilage matrix synthesis, modification, mineralisation and degradation (Ishikawa et al 1998, Himeno et al 2002, Makihira et al 2003, Bassett et al 2006.…”

Changes of hard dental and bone tissue of alveolar process in rats on the orthodontic tooth movement on the background of an experimental goiter

“…Expression augmentation of osteocalcin, alkaline phosphatase and osteal morphogenetic proteins is established at action of thyroid hormones [22][23][24]. As activity of osteal AlP grows at an intensification of processes of mineralization and in our research intensifying of resorption in an alveolar bone at reproduction of a goiter or orthodontic teeth transfer is revealed, it is possible to explain the registered increase of AlP activity by compensatory reaction on action of the general and local factors.…”

The normal and fractured physis: an anatomic and physiologic overview

“…Thyroid hormones, retinoic acid, and leptin are some systemic factors known to induce hypertrophy of chondrocytes by interacting through the bone morphogenetic protein (BMP) pathway. T3 has been shown to induce chondrocyte maturation through an increase in the levels of BMP-4 and a decrease in the levels of noggin (BMP inhibitor) [13]. Retinoic acid has also been shown to induce the maturation process of chondrocytes [14].…”