Regular ArticleDexamethasone Enhancement of Betaglycan (TGF-β Type III Receptor) Gene Expression in Osteoblast-like Cells
Abstract
Betaglycan (type III transforming growth factor-β (TGF-β) receptor) is a cell surface heparan/chondroitin sulfate proteoglycan that binds TGF-β via its core protein and is abundantly expressed in osteoblastic cells. A previous report (Centrella et al., Mol. Cell. Biol. 11, 4490-4496, 1991) showed post-translational enhancement by glucocorticoid of TGF-β binding to betaglycan. Upon the availability of the betaglycan cDNA, we investigated the effects of a glucocorticoid analogue, dexamethasone, on the regulation of betaglycan expression in osteoblast-like cells. Betaglycan mRNA was expressed as an approximately 6-kb band in MC3T3-E1 cells. The betaglycan mRNA level was enhanced severalfold by dexamethasone in these cells. The effect of dexamethasone on the betaglycan mRNA level was observed within 9 h and was sustained at least up to 48 h. The dexamethasone effect was dose-dependent, with a saturation concentration at 10-7M. Among the steroid hormones examined, dexamethasone exhibited the most potent effect on betaglycan mRNA expression, while retinoic acid also enhanced it moderately. Dexamethasone enhancement of betaglycan mRNA expression was blocked by actinomycin D, but it was not blocked by cycloheximide. Cross-linking experiments showed that dexamethasone treatment increased the binding of radiolabeled TGF-β1 to betaglycan, but did not affect binding to the type II receptor. A similar dexamethasone enhancement of betaglycan mRNA expression was also observed in a preosteoblast-like cell line, RCT1. These results suggest that dexamethasone enhances betaglycan expression at least in part via transcriptional events in osteoblasts and this would be one of the target points of glucocorticoid regulation of bone metabolism.
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Joint dysfunction and functional decline in middle age myostatin null mice
2016, BoneCitation Excerpt :Cooperation between WNT and BMP signaling pathways can further enhance the pro-osteogenic effect of each other [55–57], which would predict more active tissue remodeling in the tendon–bone insertion region of the mstn−/− mice than the wt controls. TGFBR3, also named as β-glycan, remained elevated in mstn−/− mice at all ages studied, implying enhanced activation of bone and cartilage metabolism [58–60]. Within this panel of genes, DKK1 is the only negative regulator that blocks WNT interaction with its co-receptor LRP5 and LRP6 [61].
Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn−/−), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3–6 months) to middle age (12–15 months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn−/− mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon–bone insertion in mstn−/− mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn−/− mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway.
Camurati-Engelmann disease
2011, Seminarios de la Fundacion Espanola de ReumatologiaEl síndrome de Camurati-Engelmann o displasia diafisaria progresiva es una patología que se caracteriza por la aparición de la hiperostosis de las diáfisis de los huesos largos (tibia, fémur, peroné…) que aparece de forma gradual y puede incluso afectar a las metáfisis, aunque característicamente nunca afecta a las epífisis. Además puede llegar a afectar a otros huesos, como el cráneo.
Se trata de una patología genética rara de herencia autosómica dominante, de penetrancia incompleta y expresividad variable. Se han descrito 200 afectados, de ambos sexos y de todas las razas.
Se debe a una mutación del gen que codifica el factor de crecimiento β-1.
Característicamente, la enfermedad comienza en la infancia y se caracteriza por la aparición de una marcha claudicante, dolor óseo, sobre todo en los miembros inferiores, y atrofia muscular y del tejido adiposo. Cuando el cráneo está afectado, pueden aparecer síntomas neurológicos, siendo el más frecuente la sordera.
Su diagnóstico se basa en los hallazgos clínicos más las alteraciones radiográficas típicas (ensanchamiento gradual e irregular de la diáfisis de los huesos largos). También puede ayudar en su diagnóstico la gammagrafía ósea. El diagnóstico de certeza se realizaría mediante un estudio genético de la mutación.
Los glucocorticoides son el tratamiento de elección de esta enfermedad. En el futuro, el tratamiento genético puede ser la cura de esta enfermedad.
Camurati-Engelmann disease (CED), or progressive diaphyseal dysplasia, is characterized by hyperostosis of the diaphyses of the long bones (tibiae, femora, humeri…) that appears gradually and can affect the metaphyses; the epiphyses, however, are characteristically spared. In addition, other bones, such as the skull, may be affected.
CED is a rare autosomal dominant genetic disorder. Penetrance is reduced and expressivity is variable. Over 200 patients of both genders and all races have been described.
CED is caused by a mutation in the gene encoding for transforming growth factor ß-1.
Typically, CED symptoms begin in childhood and usually consist of a waddling gait, bone pain in the lower limbs, muscular weakness and reduced subcutaneous fat. If the skull is affected, neurological symptoms can appear, the most common being hearing loss.
Diagnosis is based on clinical findings and typical radiographic changes (gradual and irregular thickening of the diaphysis of the long bones). Scintigraphy is also useful in diagnosis. Definitive diagnosis is provided by mutation analysis.
The main treatment for this disease consists of glucocorticoids. In the future, gene therapy may provide a cure for CED.
Roles for the type III TGF-β receptor in human cancer
2010, Cellular SignallingTransforming growth factor β (TGF-β) superfamily ligands have important roles in regulating cellular homeostasis, embryonic development, differentiation, proliferation, immune surveillance, angiogenesis, motility, and apoptosis in a cell type and context specific manner. TGF-β superfamily signaling pathways also have diverse roles in human cancer, functioning to either suppress or promote cancer progression. The TGF-β superfamily co-receptor, the type III TGF-β receptor (TβRIII, also known as betaglycan) mediates TGF-β superfamily ligand dependent as well as ligand independent signaling to both Smad and non-Smad signaling pathways. Loss of TβRIII expression during cancer progression and direct effects of TβRIII on regulating cell migration, invasion, proliferation, and angiogenesis support a role for TβRIII as a suppressor of cancer progression and/or as a metastasis suppressor. Defining the physiological function and mechanism of TβRIII action and alterations in TβRIII function during cancer progression should enable more effective targeting of TβRIII and TβRIII mediated functions for the diagnosis and treatment of human cancer.
Clinical and Basic Aspects of Glucocorticoid Action in Bone
2008, Principles of Bone Biology: Volume 1-2, Third EditionThis chapter deals with glucocorticoid action in bone. It describes the mechanisms involved and the resulting clinical picture of glucocorticoid action in bone. Cortisol, the glucocorticoid secreted by the adrenal gland, is essential in physiological doses for the differentiation and function of osteoblasts and osteoclasts, and it modulates the effects of other hormones and mediators of cell function, even though supraphysiological doses inhibit bone formation. These direct effects on bone, combined with effects on other systems that indirectly regulate bone metabolism, cause rapid bone loss in patients treated with glucocorticoids. The skeletal response to glucocorticoids is not disease specific, and accelerated bone loss has been described in patients with each of these diseases when they are treated with steroids. Experiments show that glucocorticoids have diverse and complex direct effects on bone and can modify the expression of a wide variety of genes in osteoblastic cells. Glucocorticoids can either stimulate or inhibit bone formation in vitro and these effects depend on the developmental stage of the model. Pharmacological doses of glucocorticoids inhibit osteoprogenitor proliferation, osteoblast renewal, osteoblast function, and osteoblast and osteocyte apoptosis; glucocorticoids also increase osteoclast formation and life span. These multiple actions lead to a decrease in bone mass and quality. It is anticipated that understanding the molecular pathways that mediate these diverse effects of glucocorticoids would enable the development of effective therapeutic modalities for glucocorticoid-induced osteoporosis.
Cbfa1 expression is enhanced by the immunosuppressant FK506 in the osteoblastic cell line: UMR106
2004, Materials Science and Engineering CAn immunosuppressant FK506 has been reported to induce osteoblast differentiation in vivo [J. Bone Miner. Res. 15 (2000) 1147]. To study the role of FK506 in osteoblast differentiation, we examined the mRNA expressions of several marker genes (Cbfa1, osteopontin, and alkaline phosphatase) in an osteoblastic cell line: UMR106-6. Results showed that the Cbfa1 (osteoblast specific transcription factor) expression in UMR cells was enhanced by treatment with FK506, promoting osteoblast differentiation. The effect was marked when simultaneous treatment with FK506 and dexamethasone was given to UMR cells comparing with the effects of treatment with each substance alone or non-treatment.
The water-soluble matrix fraction from the nacre of Pinctada maxima produces earlier mineralization of MC3T3-E1 mouse pre-osteoblasts
2003, Comparative Biochemistry and Physiology - B Biochemistry and Molecular BiologyNacre or mother of pearl is a calcified structure that forms the lustrous inner layer of some shells. We studied the biological activity of the water-soluble matrix (WSM) extracted from powdered nacre from the shell of the pearl oyster, Pinctada maxima, on the MC3T3-E1 pre-osteoblast cell line from mouse calvaria. This cell line has the ability to differentiate into osteoblasts and to mineralize in the presence of β-glycerophosphate and ascorbic acid. Cell proliferation and alkaline phosphatase activity were measured as markers of osteoblast differentiation, and mineralization was analyzed. These studies revealed that WSM stimulates osteoblast differentiation and mineralization by day 6 instead of the 21-day period required for cells grown in normal mineralizing media. We compared the activity of WSM with that of dexamethasone on this cell line. WSM can inhibit alkaline phosphatase (ALP) activity and the activity of dexamethasone on MC3T3-E1 cells. This study shows that nacre WSM could speed up the differentiation and mineralization of this cell line more effectively than dexamethasone.