The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.

TGF-beta signal transduction.

The recent identification of the SMAD family of signal transducer proteins has unravelled the mechanisms by which transforming growth factor-beta (TGF-beta) signals from the cell membrane to the nucleus. Pathway-restricted SMADs are phosphorylated by specific cell-surface receptors that have serine/threonine kinase activity, then they oligomerize with the common mediator Smad4 and translocate to the nucleus where they direct transcription to effect the cell's response to TGF-beta. Inhibitory SMADs have been identified that block the activation of these pathway-restricted SMADs.

TGF-beta signalling from cell membrane to nucleus through SMAD proteins

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

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Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

The adult skeleton regenerates by temporary cellular structures that comprise teams of juxtaposed osteoclasts and osteoblasts and replace periodically old bone with new. A considerable body of evidence accumulated during the last decade has shown that the rate of genesis of these two highly specialized cell types, as well as the prevalence of their apoptosis, is essential for the maintenance of bone homeostasis; and that common metabolic bone disorders such as osteoporosis result largely from a derangement in the birth or death of these cells. The purpose of this article is 3-fold: 1) to review the role and the molecular mechanism of action of regulatory molecules, such as cytokines and hormones, in osteoclast and osteoblast birth and apoptosis; 2) to review the evidence for the contribution of changes in bone cell birth or death to the pathogenesis of the most common forms of osteoporosis; and 3) to highlight the implications of bone cell birth and death for a better understanding of the mechanism of action and efficacy of present and future pharmacotherapeutic agents for osteoporosis.

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Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis.

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

Transforming growth factor beta is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cell cultures from fetal rat bone.

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Growth factors and the regulation of bone remodeling.

PTH was studied for its effects on bone formation in cultured rat calvariae. 0.01-10 nM PTH stimulated [3H]thymidine incorporation into DNA by up to 4.8-fold. Although continuous treatment with PTH for 24-72 h inhibited [3H]proline incorporation into collagen, transient (24 h) treatment enhanced [3H]proline incorporation into collagen 24-48 h after the hormone was removed. The collagen stimulated by PTH was type I and the effect was observed in the periosteum-free bone and was not blocked by hydroxyurea. Furthermore, treatment with 1-100 nM PTH for 24 h increased insulin-like growth factor (IGF) I concentrations by two to fourfold, and an IGF I antibody prevented the PTH stimulation of collagen synthesis, but not its mitogenic effect. In conclusion, continuous treatment with PTH inhibits calvarial collagen, whereas transient treatment stimulates collagen synthesis, and the stimulatory effect is mediated by local production of IGF I.

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Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures.

EARLY efforts to purify a bone-derived growth factor from rat bone culture medium revealed its biological and biochemical similarity to transforming growth factor-β type 1 (TGF-β1) extracted from human blood platelets. Cartilage inducing factors (CIF-A and CIF-B) from bovine bone matrix were then identified as TGF-β isoforms, and it soon became evident that bone cells synthesize TGF-βs and that bone matrix was a major repository of these factors in the organism. The TGF-β supergene family comprises at least five closely related proteins termed TGF-β1 through TGF-β5 in addition to a growing number of more distant but highly homologous growth regulators. Several of the closely related TGF-β isoforms occur in many animals, and appear to control development, growth, and differentiation in humans as well as a variety of other species. More importantly from the skeletal tissue perspective, some of the less closely related gene family members, activin-A and the bone morphogenetic proteins (BMPs), are also expres...

Transforming Growth Factor-β Gene Family Members and Bone*

Insulin-like growth factors I and II (IGF-I and -II) are polypeptides secreted by skeletal cells and are considered regulators of bone formation. IGF-I and -II were studied for their effects on collagen synthesis and degradation in cultures of intact fetal rat calvariae and on type I collagen transcript levels in osteoblast-enriched (Ob) cells from fetal rat parietal bone. IGF-I and -II increased [3H]proline incorporation into type I collagen independently of their effect on cell replication. IGF-I and -II also decreased collagen degradation in calvarial cultures. Both factors had similar actions, although IGF-I stimulated collagen synthesis at 10 nM, and IGF-II at 30 nM. In Ob cells, IGF-I and -II also increased [3H]proline incorporation into type I collagen, but the effect was seen at 100 nM, and neither factor decreased collagen degradation. Slot blot analysis of IGF-I- and IGF-II-treated cells, using a rat type I collagen cDNA probe, revealed an increase in type I collagen transcripts. In conclusion, IGF-I and -II increase bone collagen synthesis and decrease collagen degradation in cultures of intact calvariae; the effect on collagen synthesis correlates with an increase in transcript levels in Ob cells.

Thomas L. McCarthy

Papers

Transforming growth factor beta is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cell cultures from fetal rat bone.

Growth factors and the regulation of bone remodeling.

Insulin-like growth factor I mediates selective anabolic effects of parathyroid hormone in bone cultures.

Transforming Growth Factor-β Gene Family Members and Bone*

Regulatory Effects of Insulin-Like Growth Factors I and II on Bone Collagen Synthesis in Rat Calvarial Cultures