Stanniocalcin 1 Acts as a Paracrine Regulator of Growth Plate Chondrogenesis

Abstract

During embryogenesis, the expression of mammalian stanniocalcin (STC1) in the appendicular skeleton suggests its involvement in the regulation of longitudinal bone growth. Such a role is further supported by the presence of dwarfism in mice overexpressing STC1. Yet, the STC 1 inhibitory effect on growth may be related to both postnatal metabolic abnormalities and prenatal defective bone formation. In our study, we used an organ culture system to evaluate the effects of STC on growth plate chondrogenesis, which is the primary determinant of longitudinal bone growth. Fetal rat metatarsal bones were cultured in the presence of recombinant human STC (rhSTC). After 3 days, rhSTC suppressed metatarsal growth, growth plate chondrocyte proliferation and hypertrophy/differentiation, and extracellular matrix synthesis. In addition, rhSTC increased the number of apoptotic chondrocytes in the growth plate. In cultured chondrocytes, rhSTC increased phosphate uptake, reduced chondrocyte proliferation and matrix synthesis, and induced apoptosis. All these effects were reversed by culturing chondrocytes with rhSTC and phosphonoformic acid, an inhibitor of phosphate transport. The rhSTC-mediated inhibition of metatarsal growth and growth plate chondrocyte proliferation and hypertrophy/differentiation was abolished by culturing metatarsals with rhSTC and phosphonoformic acid. Taken together, our findings indicate that STC1 inhibits longitudinal bone growth directly at the growth plate. Such growth inhibition, likely mediated by an increased chondrocyte phosphate uptake, results from suppressed chondrocyte proliferation, hypertrophy/differentiation, and matrix synthesis and by increased apoptosis. Last, the expression of both STC1 and its binding site in the growth plate would support an autocrine/paracrine role for this growth factor in the regulation of growth plate chondrogenesis. Stanniocalcin (STC)2 is a glycoprotein first identified as a secretory product of the corpuscles of Stannius, an endocrine gland unique to bony fish (1, 2). The primary function of STC in fish is to prevent hypercalcemia (3) by inhibiting calcium uptake by the gills and gut and stimulating phosphate reabsorption by the kidneys (1, 4).The mammalian homolog of STC (STC1) has been found in humans, rats, and mice (5-7). Human and mouse STC1 proteins are closely related to each other (98% amino acid identity) and share 80% amino acid identity with fish STC (5). Compared with fish STC, STC1 seems to have a preferential effect on phosphate metabolism than on calcium metabolism (8, 9), with evidence suggesting that sodium-dependent P i (NaP i ) transporter(s) may be a target of STC1 activity (10). Although fish STC is primarily expressed in one organ (the corpuscle of Stannius), mammalian STC1 is virtually ubiquitous. The distribution of STC protein and/or mRNA in multiple organs such as kidney, intestine, heart, thyroid, lung, placenta, brain (11-15), and bone (with virtually undetectable serum levels) (11) would suggest a paracrine rather than an endocrine ...

Synergistic effect of p53 on TSA-induced stanniocalcin 1 expression in human nasopharyngeal carcinoma cells, CNE2

“…Other studies have demonstrated that TSA could promote apoptosis induced by Dox treatment (Karagiannis et al 2004, Rho et al 2005 via the activation of p53-signaling pathway (Magnelli et al 1995, Brantley-Finley et al 2003, Wang et al 2004. Human STC1 has been suggested to be a putative p53 downstream target and is involved in apoptosis (Wu et al 2006, Lai et al 2007, Law et al 2008, Nguyen et al 2009. In this study, the data of western blotting, real-time PCR, and p53-luciferase reporter assays showed that p53 was activated in the Dox-treated cells.…”

“…Our previous study has demonstrated the epigenetic regulation of STC1 gene expression in apoptotic cancer cells treated with histone deacetylase (HDAC) inhibitors (Law et al 2008). The possible roles of STC1 in apoptosis have been reported by different laboratories (Zhang et al 2000, Wu et al 2006, Lai et al 2007, Block et al 2009, Nguyen et al 2009). The transcriptional relationship between p53 (TP53) and STC1 has also been suggested (Lai et al 2007); however, the underlying regulatory mechanism is not clear.…”

Stanniocalcin-1 acts in a negative feedback loop in the prosurvival ERK1/2 signaling pathway during oxidative stress

“…In light of our findings, it appears that STC1 functions in response to cellular stress to control the cell death vs survival decision, and this is consistent with two recent studies. In the first, recombinant STC1 protein resulted in an increase in the number of apoptotic chondrocytes in the growth plate of cultured rat metatarsals (Wu et al, 2006), and in the other, STC1 expression was found to be regulated by p53, and was correlated with an increase in apoptosis of CNE-2 cells (Lai et al, 2007). On the basis of our findings, it seems likely that STC1 exerts proapoptotic effects in response to cellular stress through its downregulation of MEK and consequent downregulation of ERK1/2 activity.…”

Production of Calcium Maintenance Factor Stanniocalcin-1 (STC1) by the Equine Endometrium During the Early Pregnant Period

“…Surprisingly, the primary haemotrophic exchange unit of the non-invasive allantochorionic placenta, the microcotyledon, is not fully established until day 120 of pregnancy [34]. For these reasons, the amounts of endometrial STC1 secretions as well as maintenance of proper STC1 concentrations in the uterine lumen are important for conceptus development during this time period.STC1 is found in fetal bones or skeletal muscles of mice and acts as a paracrine regulator of chondrogenesis in vitro [20,21]. Transgenic mice overexpressing STC1 exhibit a significant reduction in birth weight and reduced body size in the adult [35,36], suggesting that STC1 has a regulatory role in mammalian fetal or postnatal growth.…”