The Short Stature Homeodomain Protein SHOX Induces Cellular Growth Arrest and Apoptosis and Is Expressed in Human Growth Plate Chondrocytes

Abstract

Mutations in the homeobox gene SHOX cause growth retardation and the skeletal abnormalities associated with Lé ri-Weill, Langer, and Turner syndromes. Little is known about the mechanism underlying these SHOXrelated inherited disorders of bone formation. Here we demonstrate that SHOX expression in osteogenic stable cell lines, primary oral fibroblasts, and primary chondrocytes leads to cell cycle arrest and apoptosis. These events are associated with alterations in the expression of several cellular genes, including pRB, p53, and the cyclin kinase inhibitors p21 Cip1 and p27 Kip1 . A SHOX mutant, such as seen in Lé ri-Weill syndrome patients, does not display these activities of the wild type protein. We have also shown that endogenous SHOX is mainly expressed in hypertrophic/apoptotic chondrocytes of the growth plate, strongly suggesting that the protein plays a direct role in regulating the differentiation of these cells. This study provides the first insight into the biological function of SHOX as regulator of cellular proliferation and viability and relates these cellular events to the phenotypic consequences of SHOX deficiency.

Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: A cross-sectional study using high-resolution–pQCT

“…In the human growth plate, SHOX is solely expressed in chondrocytes, as opposed to osteoblasts or osteoclasts, and plays a fundamental role in chondrocyte proliferation, hypertrophy, and apoptosis, a process that results in the formation of a cartilage framework serving as a template for osteogenesis. (43) Histopathological studies of growth plate morphology in patients with Lé ri-Weill dyschondrosteosis have showed a widespread disorganization of the normal parallel columnar arrangement of chondrocytes. (44) Speculatively, this disorganization may preferentially exert effects on the bone inside, thereby compromising trabecular architecture rather than on the perichondral bone formation that creates a collar of cortical bone.…”

X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome

“…In our study, we showed, through a precise analysis of AH with respect to target height, that patients with XrX, isoXq, and, to a lesser extent 45,X had more severe growth deficits in terms of both spontaneous growth and growth after GH treatment than those of other karyotype subgroups, highlighting the major role of X chromosome dosage in growth not only for spontaneous pre and postnatal growth but also after height improvement due to GH therapy. The effect of the SHOX gene on height is well documented, for both fetal and postnatal growth (15,16,17,18). However, little is known about the contribution of other genes to growth.…”

“…Its main effect is to promote differentiation and to stop the proliferation of hypertrophic growth plate chondrocytes. Haploinsufficiency results in the excessive proliferation of these chondrocytes and a premature fusion of the growth plate (17,18). SHOX gene function is dosage dependent.…”

Opposing roles of two isoforms of the Prx1 homeobox gene in chondrogenesis

“…Although there is no evidence to support that SHOX is alternatively spliced during chondrogenesis, it presents as a good candidate. Although both Cbf␣1 and SHOX are expressed in differentiating chondrocytes (Akiyama et al, 1999;Marchini et al, 2004), Prx1 isoforms are expressed at an earlier time in the chondrogenic process, in the prechondrogenic mesenchyme and perichondrium. Thus, Prx1 is novel in the antagonistic function of its two isoforms present during the early stages of chondrogenesis.…”