It has been known for more than a century that bone tissue adapts to functional stress by changes in structure and mass. However, the mechanism by which stress is translated into cellular activities of bone formation and resorption is unknown. We studied the response of isolated osteocytes derived from embryonic chicken calvariae to intermittent hydrostatic compression as well as pulsating fluid flow, and compared their response to osteoblasts and periosteal fibroblasts. Osteocytes, but not osteoblasts or periosteal fibroblasts, reacted to 1 h pulsating fluid flow with a sustained release of prostaglandin E2. Intermittent hydrostatic compression stimulated prostaglandin production to a lesser extent: after 6 and 24 h in osteocytes and after 6 h in osteoblasts. These data provide evidence that osteocytes are the most mechanosensitive cells in bone involved in the transduction of mechanical stress into a biological response. The results support the hypothesis that stress on bone causes fluid flow in the lacunar-canalicular system, which stimulates the osteocytes to produce factors that regulate bone metabolism.
The 5-hydroxytryptamine (5-HT) receptors 5-HT 2A , 5-HT 2B , and 5-HT 2C belong to a subfamily of serotonin receptors. Amino acid and mRNA sequences of these receptors have been published for several species including man. The 5-HT 2 receptors have been reported to act on nervous, muscle, and endothelial tissues. Here we report the presence of 5-HT 2B receptor in fetal chicken bone cells. 5-HT 2B receptor mRNA expression was demonstrated in osteocytes, osteoblasts, and periosteal fibroblasts, a population containing osteoblast precursor cells. Pharmacological studies using several agonists and antagonists showed that occupancy of the 5-HT 2B receptor stimulates the proliferation of periosteal fibroblasts. Activity of the 5-HT 2A receptor could however not be excluded. mRNA for both receptors was shown to be equally present in adult mouse osteoblasts. Osteocytes, which showed the highest expression of 5-HT 2B receptor mRNA in chicken, and to a lesser extent osteoblasts, are considered to be mechanosensor cells involved in the adaptation of bone to its mechanical usage. Nitric oxide is one of the signaling molecules that is released upon mechanical stimulation of osteocytes and osteoblasts. The serotonin analog ␣-methyl-5-HT, which preferentially binds to 5-HT 2 receptors, decreased nitric oxide release by mechanically stimulated mouse osteoblasts. These results demonstrate that serotonin is involved in bone metabolism and its mechanoregulation.The main highly differentiated cell types in bone tissue are the osteoclast, the osteoblast (OB), 1 and the osteocyte (OCY). Osteoclasts are multinucleated cells of hemopoietic origin and are related to the monocyte/macrophage (1, 2, 3). Osteoblasts on the other hand are of mesenchymal stock. Their stem and progenitor cells are present in the periosteum, endosteum, and bone marrow stroma (4). Osteocytes differentiate from osteoblasts. During the process of bone formation, a number of cells from the osteoblast layer is encapsulated in the newly formed bone matrix, whereas the other cells retract with the bone formation front. The cells that are incorporated in the bone matrix change from a cuboidal into a more stellate-shaped morphology and become osteocytes. The result of this process is a three-dimensional cellular network of osteocytes within the mineralized matrix connected to each other and to the bone surface cells by thin cell processes (5).Together these three cell types produce, maintain, and adapt or repair, if necessary, the mineralized bone matrix. Osteoclasts are capable of bone resorption, osteoblasts of bone formation. The function of osteocytes is less well understood. Because of their location within the bone matrix, osteocytes are in a prime position for the detection of mechanical inadequacies of the tissue. They are believed to act as sensor cells that translate mechanical stimuli resulting from gravitational and muscular forces on the skeleton into biochemical signals. These biochemical signals in turn activate the effectors of bone turnover, osteoclasts...
Although osteocytes are by far the most abundant cell type of bone, they are least understood in terms of function and regulation. Previous studies have concentrated on their possible role as mobilizers of bone calcium, via the process of osteocytic osteolysis. Currently, however, their possible involvement in mechanical adaptation, the process whereby bone tissue maintains maximal functional strength with minimal bone mass, is discussed. We have recently obtained experimental evidence that osteocytes are the mechanosensory cells of bone, involved in the transduction of mechanical loads into biochemical signals. Our results support the hypothesis that flow of fluid through the lacunar-canalicular system as a result of loading provides the physical signal that activates the cells.
We discovered a highly virulent variant of subtype-B HIV-1 in the Netherlands. One hundred nine individuals with this variant had a 0.54 to 0.74 log 10 increase (i.e., a ~3.5-fold to 5.5-fold increase) in viral load compared with, and exhibited CD4 cell decline twice as fast as, 6604 individuals with other subtype-B strains. Without treatment, advanced HIV—CD4 cell counts below 350 cells per cubic millimeter, with long-term clinical consequences—is expected to be reached, on average, 9 months after diagnosis for individuals in their thirties with this variant. Age, sex, suspected mode of transmission, and place of birth for the aforementioned 109 individuals were typical for HIV-positive people in the Netherlands, which suggests that the increased virulence is attributable to the viral strain. Genetic sequence analysis suggests that this variant arose in the 1990s from de novo mutation, not recombination, with increased transmissibility and an unfamiliar molecular mechanism of virulence.
Four different cell populations--designated PF, OB, OC, and PC--were isolated from calvaria of 18-day-old chick embryos for analysis of the effects of hormones on bone tissue. The cell populations were studied with histological and biochemical methods. Apart from the well-known cell types present in calvaria, a new cell type was found in the noncalcified organic matrix between the osteoblastic layer and calcified matrix. These cells were provisionally called osteocytic osteoblasts. They represent the "transition state" between osteoblasts and osteocytes. On the basis of histological studies with light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM), the PF population was considered to originate primarily from the periosteal fibroblasts, the OB population from the osteoblasts and osteocytic osteoblasts. The population of cells still present in calvaria from removal of periosteal fibroblasts and osteoblasts was called the OC population. This cell population was very much enriched with osteocytes. The fourth isolated population (PC) was a mixed population of fibroblasts, osteoblasts, and preosteoblasts. On exposure to parathyroid hormone (PTH), all four cell populations showed increased lactate production, but only the OB and OC populations displayed increased cAMP production. Prostaglandin E1 (PGE1) stimulated cAMP production in both OB and PF cells. From the results of this study it was concluded that PTH receptors are present on all of the cell types studied, but that occupancy of the receptor induces adenylate cyclase stimulation only in osteocytes and fully differentiated osteoblasts.
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