I. Introduction II. Molecular Aspects A. PPAR isotypes: identity, genomic organization and chromosomal localization B. DNA binding properties C. PPAR ligand-binding properties D. Alternative pathways for PPAR activation E. PPAR-mediated transactivation properties III. Physiological Aspects A. Differential expression of PPAR mRNAs B. PPAR target genes and functions in fatty acid metabolism C. PPARs and control of inflammatory responses D. PPARs and atherosclerosis E. PPARs and the development of the fetal epidermal permeability barrier F. PPARs, carcinogenesis, and control of the cell cycle IV. Conclusions

Peroxisome proliferator-activated receptors: nuclear control of metabolism.

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.

https://www.oarsijournal.com/article/S1063-4584(02)90801-0/pdf

Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects.

Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages

The traditional role attributed to white adipose tissue is energy storage, fatty acids being released when fuel is required. The metabolic role of white fat is, however, complex. For example, the tissue is needed for normal glucose homeostasis and a role in inflammatory processes has been proposed. A radical change in perspective followed the discovery of leptin; this critical hormone in energy balance is produced principally by white fat, giving the tissue an endocrine function. Leptin is one of a number of proteins secreted from white adipocytes, which include angiotensinogen, adipsin, acylation-stimulating protein, adiponectin, retinol-binding protein, tumour neorosis factor a, interleukin 6, plasminogen activator inhibitor-1 and tissue factor. Some of these proteins are inflammatory cytokines, some play a role in lipid metabolism, while others are involved in vascular haemostasis or the complement system. The effects of specific proteins maybe autocrine or paracrine, or the site of action maybe distant from adipose tissue. The most recently described adipocyte secretory proteins are fasting-induced adipose factor, a fibrinogen-angiopoietin-related protein, metallothionein and resistin. Resistin is an adipose tissue-specific factor which is reported to induce insulin resistance, linking diabetes to obesity. Metallothionein is a metal-binding and stress-response protein which may have an antioxidant role. The key challenges in establishing the secretory functions of white fat are to identify the complement of secreted proteins, to establish the role of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production with alterations in adiposity (obesity, fasting, cachexia). There is already considerable evidence of links between increased production of some adipocyte factors and the metabolic and cardiovascular complications of obesity. In essence, white adipose tissue is a major secretory and endocrine organ involved in a range of functions beyond simple fat storage.

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Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ

The thiazolidinediones improve insulin sensitivity in animal models and have promise as potent oral antidiabetic agents. Their clinical use has been limited because of the resulting anemia and cardiac hypertrophy. Some compounds of this class have been reported to induce bone marrow fat accumulation in animals, and this effect could account for the observed anemia. We examined the biological mechanism contributing to this phenomenon. The thiazolidinediones BRL49653 and pioglitazone induced adipocyte differentiation in the BMS2 bone marrow stromal cell line in a dose- and time-dependent manner. These actions were further enhanced by the presence of glucocorticoids and other adipogenic agonists. The thiazolidinediones increased the mRNA levels of adipocyte-specific genes, including that of their receptor, the peroxisome proliferator-activated receptor-gamma (PPAR gamma). In contrast, mRNA levels of genes encoding other PPAR family members (PPAR alpha, PPAR delta, or NUC-1) were unchanged or decreased. Thiazolidinedione treatment of primary bone marrow stromal cells elicited a comparable dose-dependent response. Using a polyclonal antibody, PPAR gamma was detected in protein lysates from adipose-rich bone marrow. Thus, thiazolidinedione directly regulates bone marrow stromal cell differentiation; induced PPAR gamma expression may play a key regulatory role in this process.

Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells.

Mature and immature forms of eight different types of blood cells are tightly packed within the spaces of bone marrow, complicating inves­ tigation of how it is efficiently regulated. Hundreds of billions of cells of the various lineages are produced daily in this vital organ and exported to other tissues via processes which are responsive to inflammation and other systemic events. Because of advances in cell separation and culture techniques, rapid progress is now being made in resolving steps in each differentiation pathway. It is even more interesting that regulatory inter­ actions between cells are being appreciated and defined in molecular terms. This review focuses on cells of the humoral immune system and those steps involved in their formation that can be observed and manipulated in culture. Purified recombinant molecules can now be used to elicit particular responses in cultured lymphocyte precursors, and the probable source of such regulatory substances is becoming clearer. Moreover, cells that comprise the inductive microenvironment of bone marrow are themselves subject to exquisite regulation. In some cases, this occurs via factors they can themselves make, i.e. autocrine regulation. Information of this kind is relevant to the treatment of a number of diseases. However, while cell culture models have made it possible to identify many molecules that affect proliferation and differentiation of B-cell precursors, they do not provide a completely accurate representation of intact bone marrow. For example, there are indications that compensatory circuits and "quality control"

Cells and Molecules that Regulate B Lymphopoiesis in Bone Marrow

A growing body of data suggests that the bone marrow stroma contains a population of pluripotent cells capable of differentiating into adipocytes, osteoblasts, and lymphohematopoietic supporting cells. In this work, the murine stromal cell lines BMS2 and +/+ 2.4 have been examined as preadipocytes and adipocytes for evidence of osteoblastic gene expression. Adipocyte differentiation has been quantitated using fluorescence activated cell sorting. Within 7–10 days of adipocyte induction by treatment with glucocorticoids, indomethacin, and methylisobutylxanthine, between 40% to 50% of the cells contain lipid vacuoles and exhibit a characteristic adipocyte morphology. Based on immunocytochemistry, both the adipocytes and preadipocytes express a number of osteoblastic markers; these include alkaline phosphatase, osteopontin, collagen (I, III), bone sialoprotein II, and fibronectin. Based on biochemical assays, the level of alkaline phosphatase expression is not significantly different between preadipocyte and adipocyte cells. However, unlike rat cell lines, dexamethasone exposure causes a dose-dependent decrease in enzyme activity. The steady-state mRNA levels of the osteoblast associated genes varies during the process of adiopogenesis. The relative level of collagen I and collagen III mRNA is lower in adipocyte-induced cells when compared to the uninduced controls. Osteocalcin mRNA is detected in preadipocytes but absent in adipocytes. These data indicate that osteoblastic gene expression is detected in cells capable of undergoing adipocyte differentiation, consistent with the hypothesis that these cell lineages are interrelated. © 1993 Wiley-Liss, Inc.

Osteoblastic gene expression during adipogenesis in hematopoietic supporting murine bone marrow stromal cells.

Lipoprotein lipase gene expression: physiological regulators at the transcriptional and post-transcriptional level.

COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity

Jeffrey M. Gimble

Papers

Peroxisome proliferator-activated receptor-gamma activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells.

Cells and Molecules that Regulate B Lymphopoiesis in Bone Marrow

Osteoblastic gene expression during adipogenesis in hematopoietic supporting murine bone marrow stromal cells.

Lipoprotein lipase gene expression: physiological regulators at the transcriptional and post-transcriptional level.

COOH-terminal disruption of lipoprotein lipase in mice is lethal in homozygotes, but heterozygotes have elevated triglycerides and impaired enzyme activity