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G Karsenty

Publications and source records attributed to G Karsenty.

At least 37 records · Page 2Linked to original sources
PubMed2001

Genetic control of skeletal development.

The skeleton is a single organ composed of >200 different elements spread throughout the body. These skeletal elements comprise two tissues: cartilage and bone. Both tissues contain specific cell type(s): chondrocytes in cartilage and osteoblasts and osteoclasts in bone. We are beginning to understand the genetic control of the differentiation and function of these cells through recent developments in mouse and human genetics, and also through the use of molecular biological and biochemical techniques. The most recent advances in terms of cell differentiation in the skeleton are presented in this review.

Animals↗
PubMed2001

Minireview: transcriptional control of osteoblast differentiation.

The last 5 yr have witnessed major progress in skeleton biology. One of these areas of progress has been the partial elucidation of the transcriptional mechanisms of osteoblast differentiation and their conservation between mouse and human. Cbfal, or runx2, a homolog of the Drosophila Runt protein serves both as the earliest transcriptional regulator of osteoblast differentiation and as controller of bone formation by already differentiated osteoblast. Moreover, Cbfal is also a hypertrophic chondrocyte differentiation factor in several skeletal elements. Although other transcription factors are likely to be involved in osteoblast differentiation, Cbfal, by the multiplicity of the role that it plays, can be viewed as the central regulator of intramembranous and endochondral ossification.

Animals↗
PubMed2001

Leptin controls bone formation through a hypothalamic relay.

Menopause favors osteoporosis and obesity protects from it. In an attempt to decipher the molecular bases of these two well-known clinical observations, we hypothesized that they meant that bone remodeling, body weight, and reproduction are controlled by identical endocrine pathways. We used mouse genetics as a tool to translate these clinical observations into a molecular hypothesis. The ob/ob and db/db mice were valuable models, since two of the three functions thought to be co-regulated are affected in these mice: they are obese and hypogonadic. Surprisingly, given their hypogonadism, both mouse mutant strains have a high bone mass phenotype. Subsequent analysis of the mechanism leading to this high bone mass revealed that it was due to an increase of bone formation. All data collected indicate that, in vivo, leptin does not act directly on osteoblasts but rather through a central pathway following binding to its specific receptors located on hypothalamic nuclei. This result revealed that bone remodeling, like most other homeostatic functions, is under hypothalamic control. The nature of the signal downstream of the hypothalamus is unknown but current experiments are attempting to identify it.

Animals↗
PubMed2001

Genetic control of skeletal development.

There are three major topics of skeleton biology. The first is skeleton patterning, which addresses how the shape and the location of each specific skeletal element is achieved. The second topic is cell differentiation in the skeleton. There are three specific cell types in the skeleton: the chondrocyte in cartilage, and the osteoblast and osteoclast in bone. The first two cell types are from mesenchymal origin while the third is from monocytic origin. The genes controlling skeleton patterning and cell differentiation are for the most part different. The third aspect of skeleton biology addresses the molecular control of the major function of the skeleton such as skeleton growth, bone mineralization and bone remodelling. Our current knowledge in each of these areas of skeleton biology will be presented in broad terms to set the course for other presentations during the symposium.

Animals↗
PubMed2000

Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes.

Type I collagen is composed of two chains, alpha1(I) and alpha2(I), encoded by two distinct genes, the alpha1(I) and alpha2(I) collagen genes, that are highly expressed in osteoblasts. In most physiological situations, alpha1(I) and alpha2(I) collagen expression is coregulated, suggesting that identical transcription factors control their expression. Here, we studied the role of Cbfa1, an osteoblast-specific transcription factor, in the control of alpha1(I) and alpha2(I) collagen expression in osteoblasts. A consensus Cbfa1-binding site, termed OSE2, is present at the same location in the alpha1(I) collagen promoter at approximately -1347 base pairs (bp) of the rat, mouse, and human genes. Cbfa1 can bind to this site, as demonstrated by electrophoretic mobility shift assay (EMSA) and supershift experiments using an anti-Cbfa1 antibody. Mutagenesis of the alpha1(I) collagen OSE2 at -1347 bp reduced the activity of a alpha1(I) collagen promoter fragment 2- to 3-fold. Moreover, multimers of this OSE2 at -1347bp confer osteoblast-specific activity to a minimum alpha1(I) collagen promoter fragment in DNA transfection experiments as well as in transgenic mice. An additional Cbfa1-binding element is present in the alpha1(I) collagen promoter of mouse, rat, and human at approximately position -372. This site binds Cbfa1 only weakly and does not act as a cis-acting activator of transcription when tested in DNA transfection experiments. Similar to alpha1(I) collagen, the mouse alpha2(I) collagen gene contains multiple OSE2 sites, of which one is conserved across multiple species. In EMSA, Cbfa1 binds to this site and multimers of this alpha2(I) OSE2 element confer osteoblast-specific activity to the minimum alpha1(I) collagen promoter in DNA transfection experiments. Thus, our results suggest that Cbfa1 is one of the positive regulators of the osteoblast-specific expression of both type I collagen genes.

3T3 Cells↗
PubMed2000

The osteoblast: a sophisticated fibroblast under central surveillance.

The study of the biology of osteoblasts, or bone-forming cells, illustrates how mammalian genetics has profoundly modified our understanding of cell differentiation and physiologic processes. Indeed, genetic-based studies over the past 5 years have revealed how osteoblast differentiation is controlled through growth and transcription factors. Likewise, the recent identification, using mutant mouse models, of a central component in the regulation of bone formation expands our understanding of the control of bone remodeling. This regulatory loop, which involves the hormone leptin, may help to explain the protective effect of obesity on bone mass in humans. In addition, it provides a novel physiologic concept that may shed light on the etiology of osteoporosis and help to identify new therapeutic targets.

Animals↗
PubMed2000

Genetic ablation of parathyroid glands reveals another source of parathyroid hormone.

The parathyroid glands are the only known source of circulating parathyroid hormone (PTH), which initiates an endocrine cascade that regulates serum calcium concentration. Glial cells missing2 (Gcm2), a mouse homologue of Drosophila Gcm, is the only transcription factor whose expression is restricted to the parathyroid glands. Here we show that Gcm2-deficient mice lack parathyroid glands and exhibit a biological hypoparathyroidism, identifying Gcm2 as a master regulatory gene of parathyroid gland development. Unlike PTH receptor-deficient mice, however, Gcm2-deficient mice are viable and fertile, and have only a mildly abnormal bone phenotype. Despite their lack of parathyroid glands, Gcm2-deficient mice have PTH serum levels identical to those of wild-type mice, as do parathyroidectomized wild-type animals. Expression and ablation studies identified the thymus, where Gcm1, another Gcm homologue, is expressed, as the additional, downregulatable source of PTH. Thus, Gcm2 deletion uncovers an auxiliary mechanism for the regulation of calcium homeostasis in the absence of parathyroid glands. We propose that this backup mechanism may be a general feature of endocrine regulation.

Animals↗
PubMed2000

MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1.

The bone-specific transcription factor, Cbfa1, regulates expression of the osteocalcin (OCN) gene and is essential for bone formation. However, little is known about the mechanisms regulating Cbfa1 activity. This work examines the role of the MAPK pathway in regulating Cbfa1-dependent transcription. Stimulation of MAPK by transfecting a constitutively active form of MEK1, MEK(SP), into MC3T3-E1 preosteoblast cells increased endogenous OCN mRNA, while a dominant negative mutant, MEK(DN), was inhibitory. MEK(SP) also stimulated activity of a 147-base pair minimal OCN promoter, and this stimulation required an intact copy of OSE2, the DNA binding site for Cbfa1. Effects of MEK(SP) were specific to Cbfa1-positive osteoblast-like cells. A purified His-tagged Cbfa1 fusion protein was directly phosphorylated by activated recombinant MAPK in vitro. Furthermore, (32)P metabolic labeling studies demonstrated that MEK(SP) clearly enhanced phosphorylation of Cbfa1 in intact cells, while MEK(DN) decreased phosphorylation. The specific MEK1/MEK2 inhibitor, PD98059, inhibited extracellular matrix-dependent up-regulation of the OCN promoter, indicating that the MAPK pathway and, presumably, Cbfa1 phosphorylation are also required for responsiveness of osteoblasts to extracellular matrix signals. This study is the first demonstration that Cbfa1 is controlled by MAPKs and suggests that this pathway has an important role in the control of osteoblast-specific gene expression.

Animals↗
PubMed2000

Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass.

Gonadal failure induces bone loss while obesity prevents it. This raises the possibility that bone mass, body weight, and gonadal function are regulated by common pathways. To test this hypothesis, we studied leptin-deficient and leptin receptor-deficient mice that are obese and hypogonadic. Both mutant mice have an increased bone formation leading to high bone mass despite hypogonadism and hypercortisolism. This phenotype is dominant, independent of the presence of fat, and specific for the absence of leptin signaling. There is no leptin signaling in osteoblasts but intracerebroventricular infusion of leptin causes bone loss in leptin-deficient and wild-type mice. This study identifies leptin as a potent inhibitor of bone formation acting through the central nervous system and therefore describes the central nature of bone mass control and its disorders.

Animals↗
PubMed2000

The mammalian basic helix loop helix protein HES-1 binds to and modulates the transactivating function of the runt-related factor Cbfa1.

Drosophila Runt is the founding member of a family of related transcription factors involved in the regulation of a variety of cell-differentiation events in invertebrates and vertebrates. Runt-related proteins act as both transactivators and transcriptional repressors, suggesting that context-dependent mechanisms modulate their transcriptional properties. The aim of this study was to elucidate the molecular mechanisms that contribute to the regulation of the functions of the mammalian Runt-related protein, Cbfa1. Here we provide the first demonstration that Cbfa1 (as well as the related protein, Cbfa2/AML1) physically interacts with the basic helix loop helix transcription factor, HES-1, a mammalian counterpart of the Drosophila Hairy and Enhancer of split proteins. This interaction is mediated by the carboxyl-terminal domains of Cbfa1 and HES-1, but does not require their respective tetrapeptide motifs, WRPY and WRPW. Our studies also show that HES-1 can antagonize the binding of Cbfa1 to mammalian transcriptional corepressors of the Groucho family. Moreover, HES-1 can potentiate Cbfa1-mediated transactivation in transfected cells. Taken together, these findings implicate HES-1 in the transcriptional functions of Cbfa1 and suggest that the concerted activities of Groucho and HES proteins modulate the functions of mammalian Runt-related proteins.

Basic Helix-Loop-Helix Proteins↗
PubMed2000

A neuro (endo)crine regulation of bone remodeling.

Bone remodeling is the normal physiologic process that is used by vertebrates to maintain a constant bone mass during the period bracketed by the end of puberty and the onset of gonadal failure in later life. Besides the well-characterized and critical process of local regulation of bone remodeling, achieved by autocrine and paracrine mechanisms, recent genetic studies have shown that there is a central control of bone formation, mediated by a neuroendocrine mechanism. This central regulation involves leptin, an adipocyte-secreted hormone that controls body weight, reproduction and bone remodeling, and which binds to and exerts its effect through the cells of the hypothalamic nuclei in the brain. This genetic result in mice is in line with clinical observations in humans and generates a whole new direction of research in bone physiology. BioEssays 22:970-975, 2000.

Animals↗
PubMed2000

Role of Cbfa1 in osteoblast differentiation and function.

Among the multiple cell lineages whose differentiation is affected by a runt-related gene the osteoblast is a relative newcomer. Molecular biology, developmental biology and mouse and human genetic studies have demonstrated that Cbfa1 is a critical regulator of osteoblast differentiation in vertebrates. Cbfa1 is not only a differentiation factor but also a regulator of bone formation by differentiated osteoblasts beyond development. Thus, Cbfa1 controls osteogenesis at multiple stages.

Amino Acid Sequence↗
PubMed2000

The central regulation of bone remodeling.

For a long time bone remodeling has been thought to be mainly an autocrine-paracrine phenomenon. Yet bone resorption mechanisms are under the control of hormones, suggesting that the same might be true for bone formation. The recent development of molecular endocrinology uncovers a common, central regulation of bone formation, body weight and reproduction mediated by leptin.

Animals↗