Osteocyte

An osteocyte, a star-shaped cell, is the most numerous cell found in mature bone, and can live as long as the organism itself. Osteocytes have an average half life of 25 years, they do not divide, and they are derived from osteoprogenitors, some of which differentiate into active osteoblasts. In mature bone, osteocytes and their processes reside inside spaces called lacunae and canaliculi, respectively. Cells contain a nucleus and a thin ring of cytoplasm. When osteoblasts become trapped in the matrix they secrete, they become osteocytes. Osteocytes are networked to each other via long cytoplasmic extensions that occupy tiny canals called canaliculi, which are used for exchange of nutrients and waste through gap junctions. The space that an osteocyte occupies is called a lacuna (Latin for a pit). Although osteocytes have reduced synthetic activity and, like osteoblasts are not capable of mitotic division, they are actively involved in the routine turnover of bony matrix, through various mechanosensory mechanisms. They destroy bone through a rapid, transient (relative to osteoclasts) mechanism called osteocytic osteolysis. Osteoblasts/osteocytes develop in mesenchyme. Hydroxyapatite, calcium carbonate and calcium phosphate is deposited around the cell.

Morphology
Osteocytes have a stellate shape, and in humans they are approximately 9 micrometers long in the short axis by 20 micrometers long in the long axis. The cell body varies in size from 5-20micrometers in diameter and contain 40-60 cell processes per cell ,with a cell to cell distance between 20-30 micrometers. A mature osteocyte contains a single nucleus that is located toward the vascular side and has one or two nucleoli and a membrane. The cell also exhibits a reduced size endoplasmic reticulum, Golgi apparatus and mitochondria, and cell processes that radiate towards the mineralizing matrix. Osteocytes form an extensive connecting syncitial network via small cytoplasmic/dendritic processes in canaliculi.

Origin
Osteocytes are derived from mesenchymal stem cells within the bone marrow. The fossil record shows that osteocytes were present in bones of jawless fish 400-250 million years ago, and dinosaurs 80 million years old. Therefore, osteocytes have been used to estimate the size of the genome of extinct species.

During bone formation, an osteoblast is left behind and buried in the bone matrix as an "osteoid osteocyte", which maintains contact with the osteoblasts through extending cellular processes. The process of osteocytogenesis is largely unknown, but the following molecules have been shown to play a crucial role in the production of healthy osteocytes, either in correct numbers or specific distributions: Matrix Metalloproteinases (MMPs), Dentin Matrix Protein 1 (DMP-1), Osteoblast/Osteocyte factor 45 (OF45), Klotho gene, TGF Beta inducile factor (TIEG), Lysophosphatidic acid (LPA), E11 antigen, and Oxygen. The transformation from motile osteoblast to entraped osteocyte takes about three days, and during this time, the cell produces a volume of extracellular matrix three times its own cellular volume, which results in 70% volume reduction in the mature osteocyte cell body compared to the original osteoblast volume. 10-20% of osteoblasts differentiate into osteocytes. The cell undergoes a dramatic transformation from a polygonal shape to a cell that extends dendrites toward the mineralizing front, followed by dendrites that extend to either the vascular space or bone surface. The embedded "osteoid-osteocyte" must do two functions simultaneously: regulate mineralization and form connective dendritic processes, which requires cleavage of collagen and other matrix molecules. As the osteoblast transitions to an osteocyte, alkaline phosphatase is reduced, and casein kinase II is elevated, as is osteocalcin. Those osteoblasts on the bone surface that are destined for burial as osteocytes slow down matrix production, and are buried by neighboring osteoblasts that continue to produce matrix actively. Palumbo et al.(1990) distinguish three cell types from osteoblast to mature osteocyte: type I preosteocyte (osteoblastic osteocyte), type II preosteocyte (osteoid osteocyte), and type III preosteocyte (partially surrounded by mineral matrix.

Osteocytes appear to be enriched in proteins that are resistant to hypoxia, which appears to be due to their embedded location and restricted oxygen supply Oxygen tension may regulate the differentiation of osteoblasts into osteocytes, and osteocyte hypoxia may play a role in disuse-mediated bone resorption.

Function
Although osteocytes are relatively inert cells, they are capable of molecular synthesis and modification, as well as transmission of signals over long distances, in a way similar to the nervous system. They are the most common cell type in bone (31,900 mm-3 in bovine bone to 93,200 mm-3 in rat bone). Most of the receptor activities that play an important role in bone function are present in the mature osteocyte. Osteocytes contain glutamate transporters that produce nerve growth factors after bone fracture, which provides evidence of a sensing and information transfer system. When osteocytes were experimentally destroyed, the bones showed a significant increase in bone resorption, decreased bone formation, trabecular bone loss, and loss of response to unloading.

Osteocytes are thought to be mechanosensor cells that control the activity of osteoblasts and osteoclasts within a basic multicellular unit (BMU), a temporary anatomic structure where bone remodeling occurs. Osteocytes generate an inhibitory signal that is passed through their cell processes to osteoblasts for recruitment to enable bone formation.

Osteocyte specific proteins such as sclerostin have been shown to function in mineral metabolism, as well as other molecules such as PHEX, DMP-1, MEPE, and FGF-23, which are highly expressed by osteocytes and regulate phosphate and biomineralization.

The osteocyte is an important regulator of bone mass and a key endocrine regulator of phosphate metabolism.

Sclerostin
Osteocytes synthesize sclerostin, a secreted protein that inhibits bone formation by binding to LRP5/LRP6 coreceptors and blunting Wnt signaling. Sclerostin, the product of the SOST gene, is the first mediator of communication between osteocytes, bone forming osteoblasts and bone resorbing osteoclasts, critical for bone remodeling. Only osteocytes express sclerostin, which acts in a paracrine fashion to inhibit bone formation. Sclerostin is inhibited by parathyroid hormone (PTH) and mechanical loading. Sclerostin anatagonizes the activity of BMP (bone morphogenetic protein),a citokine that induces bone and cartilage formation.

Osteocyte Apoptosis and Associated Pathologies
Osteocytes die as a consequence of senescence, degeneration/necrosis, apoptosis(programmed cell death), and/or osteoclastic engulfment. The percentage of dead osteocytes in bone increases with age from less than 1% at birth to 75% after age 80. Osteocyte apoptosis is thought to be related to decreased mecanotransduction, which possibly leads to the development of osteoporosis. Apoptotic osteocytes release apoptotic bodies expressing RANKL to recruit osteoclasts.

Mechanical loading increases osteocyte viability in vitro, and contributes to solute transport through the lacuno-canalicular system in bone, which enhances oxygen and nutrient exchange and diffusion to osteocytes. Skeletal unloading has been shown to induce osteocyte hypoxia in vivo, this is when osteocytes undergo apoptosis and recruit osteoclasts to resorb bone. Microdamage in bone occurs as the result of repetitive events of cycling loading, and appears to be associated with osteocyte death by apoptosis, which appear to secrete a signal to target osteoclasts to perform remodeling at a damaged site. Under normal conditions, osteocytes express high amounts of TGF-β and thus repress bone resorption, but when bone grows old, the expression levels of TGF-β decrease, and the expression of osteoclast-stimulatory factors, such as RANKL and M-CSF increases, bone resorption is then enhanced, leading to net bone loss.

Mechanical stimulation of osteocytes results in opening of hemichannels to release PGE2 and ATP, among other biochemical signaling molecules, which play a crucial role in maintaining the balance between bone formation and resorption. Osteocyte cell death can occur in association with pathologic conditions such as osteoporosis and osteoarthritis, which leads to increased skeletal fragility, linked to the loss of ability to sense microdamage and/or signal repair. Oxygen deprivation that occurs as the result of immobilization (bed rest), glucocorticoid treatment, and withdrawal of oxygen have all been shown to promote osteocyte apoptosis.