Search

Adipocytes, osteoblasts and chondrocytes derive from common mesenchymal stem cells. A number of factors were reported to regulate differentiation of multiple cell types among adipocytes, osteoblasts and chondrocytes. Thiazolidinediones are prescribed to treat diabetes in obese subjects, but recent clinical data suggested that it increases a risk of bone fracture especially in postmenopausal women. Here, we will review recent advances in the researches of mutual connection between adipocytes and bone metabolism.

Dyslipidemia and osteoporosis are etiologically related to each other. Experiments show that oxidized LDL suppresses the differentiation of bone marrow stromal cells to osteoblasts, while it promotes that to adipocytes, which may result in fatty marrow and bone mass reduction. Inactivation of LRP5÷6 is linked to hypercholesterolemia as well as bone mass reduction, indicating the involvement of Wnt signaling in both disorders. A few clinical studies suggest that high serum triglyceride levels may lower the risk of vertebral fractures. Metabolic syndrome, especially visceral fat accumulation, may have a beneficial effect on bone possibly through mechanical stress from gravity, as long as patients are devoid of advanced type 2 diabetes and are less affected by hyperglycemia or oxidative stress.

Ever since oxidized low density lipoprotein (LDL) was first identified in human atherosclerotic lesions, probucol was found to suppress the development of atherosclerosis in animals, and LDL incubated with vascular cells underwent oxidative modification, the so-called oxidative modification hypothesis of atherogenesis was nurtured, and a number of significant pieces of evidence have accumulated to suggest the underlying contributions of oxidized LDL to the development of atherosclerotic diseases. Recently, oxidized LDL in blood circulation can be measured, and plasma-oxidized LDL is a well-known risk marker of cardiovascular diseases. Oxidized LDL-mediated macrophage foam cell formation is probably attributed to the lack of down-regulation of oxidized LDL receptors, but high-density lipoprotein (HDL) or apolipoprotein A1-mediated cholesterol efflux from cells is also promoted, probably by oxidized LDL. This may be why macrophage cholesterol accumulation induced by oxidized LDL does not advance unilaterally. However, such a suppressive effect of HDL may be inhibited once HDL undergoes inflammatory or oxidative modification because oxidized HDL could be dysfunctional. Remnant lipoproteins can be taken up by macrophages without oxidative modification in contrast to LDL, and remnant lipoproteins exhibit many atherogenic actions similar to oxidized LDL. However, oxidized remnant lipoproteins do not function as an effective material of foam cells. Recent papers have demonstrated that oxidized phospholipid (PL)/apolipoprotein B, playing a potential role in predicting cardiovascular diseases, correlates strongly with lipoprotein (a) [(Lp (a)] because Lp (a) is susceptible to binding to oxidized PL, and oxidized Lp (a) is also detected in human coronary atherosclerotic lesions. Although many lines of evidence support the oxidized LDL hypothesis of atherosclerosis, we face important problems to be overcome, such as the fact that oxidized lipoproteins may not be relevant to human atherosclerosis because antioxidation treatments with vitamins do not necessarily prevent human cardiovascular diseases. Oxidized LDL could play a role in the initiation of foam cell generation, but become less important in the later stages of atherosclerotic disease. Taken together, we have to keep an open mind regarding the incompletely understood pathogenesis in association with oxidized lipoproteins.

Oxidized low-density lipoprotein (OxLDL) is thought to be involved in atherosclerotic lesion formation. We established a monoclonal antibody, DLH3, that recognizes oxidized phosphatidylcholine (OxPC) formed in OxLDL. A sensitive method for detecting OxLDL was enabled by a sandwich ELISA procedure utilizing DLH3 together with an anti-apoB antibody. Using the method, we demonstrated the presence of OxLDL in human circulating plasma for the first time, and the plasma OxLDL level in healthy subjects was estimated to be about 0.1 ng/microgram LDL protein. OxLDL levels in patients with acute myocardial infarction are more than 3 times higher than in controls. Thus the plasma OxLDL level could be a good marker for cardiovascular disease. There are multiple metabolic enzymes for OxPC in plasma. We demonstrated that lecithin: cholesterol acyltransferase (LCAT) is capable of metabolizing OxPC molecules in OxLDL, and that the plasma OxLDL level in patients with familial LCAT deficiency was about 3.5 times higher than in controls. OxLDL in vivo is likely to be metabolized by enzymatic activities in plasma, the reticuloendothelial system including Kupffer cells, and immunological responses. The OxLDL levels determined by this analytical procedure would reflect the physiologic balance between oxidative modification of LDL and metabolic clearance of OxLDL.

Recent progress in the study of atherosclerosis revealed that the proatherogenic property of LDL is attributable to oxidized LDL. Macrophages recruited to vascular wall phagocytose oxidized LDL and transformed into foam cells, which is a hallmark of atheroma. Endothelial cells also binds oxidized LDL and changes its phenotype to the status of "endothelial dysfunction." We successfully cloned the endothelial receptor for oxidized LDL, designated LOX-1. LOX-1-mediated action of oxidized LDL induces the decrease in NO release and the increased expression of adhesion molecules, which are typical changes in endothelial dysfunction. The expression of LOX-1 is quite inducible. Proinflammatory cytokines, etc. induce the expression of LOX-1 in vitro; and proatherogenic conditions, e.g., hypertension, hyperlipidemia, and diabetes, induce the expression of LOX-1 in vivo. This manner of expression suggests the importance of LOX-1 in pathological settings. LOX-1 binds not only oxidized LDL, but also binds apoptotic cells and activated platelets through the interaction with anionic phospholipids. This property might bridge atherosclerosis and thrombosis. A novel system to detect LOX-1 ligand in plasma detected the increased level of LOX-1 ligand in hypercholesterolemic rabbits compared with normal ones. This system might be useful to predict the status of endothelial function and the risk of ischemic heart disease.

Since autonomic dysfunction in familial amyloidotic polyneuropathy (FAP) Type I is recognized in the early stage of FAP patients and restricts their daily life, we developed various therapies for various autonomic manifestations: Loading glucose was often effective for faintness caused by hypoglycemia and erythropoietin was also good therapy for orthostatic hypotension as well as anemia found in the end stage of FAP patients. Stoma and nasal drop of L-threo-DOPS were useful to control diarrhea and orthostatic hypotension. Duplex ultrasonography of the 4 vessels revealed that reverse flow was always recognized in FAP patients with faintness, which was effectively treated by the administration of L-threo-DOPS. Orthotopic liver transplantation revealed effective therapy for autonomic dysfunction in FAP patients. Precise analysis of protein metabolism in FAP patients revealed that among apolipoproteins, only apolipoprotein AII decreased as the progression of the disease and high density lipoprotein gained the negative charge by agarose electrophoresis study. Concerning low density lipoprotein (LDL) study, only variant transthyretin in the circulation associated with LDL in FAP patients, suggesting that LDL may play an important role in the amyloid formation of FAP.

Calcium pyrophosphate dihydrate (CPPD) crystal-induced inflammation subsides spontaneously, and there have been few reports on its mechanism. It has recently been proposed that lipoproteins in the inflammatory synovial fluid played a role in the recovery from crystal-induced arthritis. This study investigated the inhibitory effect of lipoprotein on the inflammation-inducing activity of CPPD crystals in vitro and in vivo. Lipoproteins (very low density lipoprotein--VLDL, and low density lipoprotein-LDL) were isolated from human serum (in vitro) and rat serum (in vivo) by the sequential ultracentrifugal technique. In the in vitro studies, saline with lipoproteins was mixed with CPPD crystals, and co-incubated with isolated polymorphonuclear leukocytes (PMN). The production of superoxide anion (O-(2)) was measured as an index of inflammatory activity. In the in vivo studies, suspensions of CPPD crystals and rat lipoprotein solutions, were injected into the rat air pouch. The total number of white blood cells (WBC), crystal-containing WBCs, and concentrations of beta-glucronidase and prostaglandin (PG) E2, were measured. In the in vitro studies, O-(2) production by PMNs was more significantly suppressed after treating the CPPD crystals with VLDL or LDL than when the crystals were not treated with VLDL or LDL. In the in vivo studies, treatment of the CPPD crystals with lipoproteins significantly decreased the number of WBC and crystal-containing WBC, as well as the concentration of beta-glucronidase, and tended to depress the concentration of PGE2. These findings suggested that lipoproteins, especially LDL in inflammatory synovial fluid played an important role in the recovery from CPPD crystal-induced arthritis.

Low-density lipoprotein (LDL) at a concentration of 100 micrograms/mL, which is near the dissociation constant (Kd) of LDL-binding, had a maximal stimulatory effect on agonist-induced platelet aggregation. Anti-LDL receptor monoclonal antibody (C-7), like native LDL, induces a transient increase in intracellular Ca2+ and a shape change of human platelets. On the other hand, high-density lipoprotein (HDL) inhibited platelet function. ApoE-rich HDL, as well as, apoE.DMPC potently inhibited platelet aggregation in a dose-dependent manner. ApoE.DMPC stimulated the release of cholesterol into the supernatant, suggesting that apoE plays a major role in the inhibitory effect of apoE-rich HDL in platelet function, presumably due to the release of cholesterol from the plasma membrane.

The purpose of the present study was to define the effect of low density lipoprotein (LDL) on progesterone (P) synthesis and on intracellular cholesterol content using monolayer cultured human luteal cells. When cultured in TC199 containing 10% lipoprotein poor serum (LPPS), P production decreased as culture time passed. In the presence of hCG, it also decreased, but slowly. In the presence of LDL, P production was kept at a higher level. Intracellular cholesterol content in luteal cells was measured by gas chromatography. The cholesterol content of luteal cells in a 4 day LPPS culture was higher than that in a 10 day LPPS culture. The cholesterol content in a 10 day LPPS culture with LDL was higher than that in a 10 day LPPS culture. The cholesterol content in a 10 day LPPS culture with hCG had a tendency to be lower than that in a 10 day LPPS culture, but there was no statistical difference (p less than 0.1). It was concluded that LDL was utilized in supplying intracellular cholesterol to luteal cells as a substrate for P synthesis. And in a state of LDL depletion in the medium, the luteal cells produced a small amount of P utilizing intracellular cholesterol. It was estimated from the results of the present study that hCG enhanced utilization of intracellular cholesterol.