Osteocyte

{{Short description|Cell type}}{{Infobox cell | Name = Osteocyte | Latin = Osteocytus | Image = Transverse section of bone en.svg | Caption = Transverse section of a bone | Image2 = Bone_cells_-_Osteocytes_1_--_Smart-Servier.png | Caption2 = Illustration showing a single osteocyte | Precursor = | System = | Location = Bone }} An '''osteocyte''', an oblate-shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself.<ref name="Tate_2004"/> The adult human body has about 42 billion of them.<ref>{{Cite journal|title = Quantifying the osteocyte network in the human skeleton|journal = Bone|date = 2015-06-01|issn = 1873-2763|pmid = 25708054|pages = 144–150|volume = 75|doi = 10.1016/j.bone.2015.02.016|first1 = Pascal R.|last1 = Buenzli|first2 = Natalie A.|last2 = Sims}}</ref> Osteocytes do not divide and have an average half life of 25 years. They are derived from osteoprogenitor cells, some of which differentiate into active osteoblasts (which may further differentiate to osteocytes).<ref name="Tate_2004"/> Osteoblasts/osteocytes develop in mesenchyme.

In mature bones, osteocytes and their processes reside inside spaces called lacunae (Latin for a ''pit'') and canaliculi, respectively.<ref name="Tate_2004">{{cite journal |last1=Tate |first1=M. L. |last2=Adamson |first2=J. R. |last3=Tami |first3=A. E. |last4=Bauer |first4=T. W. |year=2004 |title=Cells in Focus, The osteocyte |journal=International Journal of Biochemistry & Cell Biology |volume=36 |issue=1 |pages=1–8 |doi=10.1016/S1357-2725(03)00241-3 |pmid=14592527 }}</ref> Osteocytes are simply osteoblasts trapped in the matrix that they secrete. They 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.

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. Hydroxyapatite, calcium carbonate and calcium phosphate is deposited around the cell.

==Structure== Osteocytes have a stellate shape, approximately 7 micrometers deep and wide by 15 micrometers in length.<ref name="Sugawara, Y 2005">{{cite journal | last1 = Sugawara | first1 = Y | last2 = Kamioka | first2 = H | last3 = Honjo | first3 = T | last4 = Tezuka | first4 = K | last5 = Takano-Yamamoto | first5 = T | year = 2005 | title = Three dimensional reconstruction of chick calvarial osteocytes and their cell processes using confocal microscopy | journal = Bone | volume = 36 | issue = 5| pages = 877–83 | doi=10.1016/j.bone.2004.10.008 | pmid=15820146}}</ref> The cell body varies in size from 5–20 micrometers in diameter and contain 40–60 cell processes per cell,<ref>{{cite journal | last1 = Tanaka-amioka | first1 = K | last2 = Kamioka | first2 = H | last3 = Ris | first3 = H | last4 = Lim | first4 = SS | year = 1998 | title = Osteocyte shape is dependent on actin filaments and osteocyte processes are unique actin-rich projections | journal = J. Bone Miner. Res. | volume = 13 | issue = 10| pages = 1555–68 | doi=10.1359/jbmr.1998.13.10.1555| pmid = 9783544 | s2cid = 5972946 | doi-access = free }}</ref> with a cell to cell distance between 20–30 micrometers.<ref name="Sugawara, Y 2005"/> A mature osteocyte contains a single nucleus that is located toward the vascular side and has one or two nucleoli and a membrane.<ref name="Dudley_1961"/> The cell also exhibits a reduced size endoplasmic reticulum, Golgi apparatus and mitochondria, and cell processes that radiate largely towards the bone surfaces in circumferential lamellae, or towards a haversian canal and outer cement line typical of osteons in concentric lamellar bone.<ref name="Dudley_1961">{{cite journal | last1 = Dudley | first1 = HR | last2 = Spiro | first2 = D | year = 1961 | title = The fine structure of bone cells | journal = The Journal of Biophysical and Biochemical Cytology | volume = 11 | issue = 3| pages = 627–649 | doi=10.1083/jcb.11.3.627| pmid = 19866598 | pmc = 2225143 }}</ref> Osteocytes form an extensive lacunocanalicular network within the mineralized collagen type I matrix, with cell bodies residing within lacunae, and cell/dendritic processes within channels called canaliculi.<ref name="Noble_2008">{{cite journal | last1 = Noble | first1 = SN | year = 2008 | title = The osteocyte lineage | journal = Archives of Biochemistry and Biophysics | volume = 473 | issue = 2| pages = 106–111 | doi=10.1016/j.abb.2008.04.009| pmid = 18424256 }}</ref>

thumb|An osteocyte in rat bone exposed by resin cast etching

==Development== The fossil record shows that osteocytes were present in bones of jawless fish 400 to 250 million years ago.<ref name="Pajevic_2009">{{cite journal | last1 = Divieti Pajevic | first1 = P | year = 2009 | title = Regulation of Bone Resorption and Mineral Homeostasis by Osteocytes | journal = IBMS BoneKEy | volume = 6 | issue = 2| pages = 63–70 | doi=10.1138/20090363}}</ref> Osteocyte size has been shown to covary with genome size; and this relationship has been used in paleogenomic research.<ref name="Organ_2007">{{cite journal | last1 = Organ | first1 = C. L. | last2 = Shedlock | first2 = A. M. | last3 = Meade | first3 = A. | last4 = Pagel | first4 = M. | last5 = Edwards | first5 = S. V. | year = 2007 | title = Origin of avian genome size and structure in nonavian dinosaurs | journal = Nature | volume = 446 | issue = 7132| pages = 180–184 | doi=10.1038/nature05621 | pmid=17344851| bibcode = 2007Natur.446..180O | s2cid = 3031794 }}</ref>

During bone formation, an osteoblast is left behind and buried in the bone matrix as an "osteoid osteocyte", which maintains contact with other osteoblasts through extended cellular processes.<ref name="Palumbo_1990">{{Cite journal |doi = 10.1159/000146907|title = Osteocyte Differentiation in the Tibia of Newborn Rabbit: An Ultrastructural Study of the Formation of Cytoplasmic Processes|journal = Cells Tissues Organs|volume = 137|issue = 4|pages = 350–358|year = 1990|last1 = Palumbo|first1 = Carla|last2 = Palazzini|first2 = Silvana|last3 = Zaffe|first3 = Davide|last4 = Marotti|first4 = Gastone|pmid = 2368590|hdl = 11380/638791|hdl-access = free}}</ref> Although recently it was shown that vascular smooth muscle cells drive osteocyte differentiation,<ref> {{cite journal | vauthors = Fernandes CJ, Silva RA, Ferreira MR, Fuhler GM, Peppelenbosch MP, van der Eerden BC, Zambuzzi WF| title = Vascular smooth muscle cell-derived exosomes promote osteoblast-to-osteocyte transition via β-catenin signaling. | journal = Experimental Cell Research | volume = 442 | article-number = 114211| date = August 2024 | pmid = 39147261| doi = 10.1016/j.yexcr.2024.114211 | hdl = 11449/298906| hdl-access = free}}</ref> most aspects of osteocytogenesis remain largely unknown. Various molecules have been reported to be involved. Examples include matrix metalloproteinases (MMPs), dentin matrix protein 1 (DMP-1), osteoblast/osteocyte factor 45 (OF45), Klotho, TGF-beta inducible factor (TIEG), lysophosphatidic acid (LPA), E11 antigen, and oxygen.<ref name="Noble_2008"/> 10–20% of osteoblasts differentiate into osteocytes.<ref name="Noble_2008"/> 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.<ref name="Franz_2006">{{cite journal | last1 = Franz-Odendaal | first1 = T | last2 = Hall | first2 = B | last3 = Witten | first3 = PE | year = 2006 | title = Buried Alive: How Osteoblasts Become Osteocytes | journal = Developmental Dynamics | volume = 235 | issue = 1| pages = 176–190 | doi=10.1002/dvdy.20603 | pmid=16258960| s2cid = 42563087 | doi-access = free }}</ref> thumb|HAADF-STEM electron image of a maturing osteocyte (preosteocyte or osteoid osteocyte) at the bone surface, appearing directly above osteoblast-like precursor cells (decalcified matrix). Note the elongated cell processes that are surrounded by the collagen type I matrix and already crossing lamellar boundaries as collagen (and eventually mineral) continues to entomb the cell. |350x350px 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).<ref name="Franz_2006"/> 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.<ref name="Bonewald_2011"/> The transformation from motile osteoblast to entrapped 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.<ref>{{cite journal | last1 = Palumbo | first1 = C | year = 1986 | title = A three dimensional ultrastructural study of osteoid-osteocytes in the tibia of chick embryos | journal = Cell and Tissue Research | volume = 246 | issue = 1 | pages = 125–131 | doi=10.1007/bf00219008| pmid = 3779795 | s2cid = 12594545 | hdl = 11380/695556 | hdl-access = free }}</ref> 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.<ref name="Bonewald_2011">{{cite journal | last1 = Bonewald | first1 = L | year = 2011 | title = The Amazing Osteocyte | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 2| pages = 229–238 | doi=10.1002/jbmr.320 | pmid=21254230 | pmc=3179345}}</ref> As the osteoblast transitions to an osteocyte, alkaline phosphatase is reduced, and casein kinase II is elevated, as is osteocalcin.<ref name="Bonewald_2011"/>

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.<ref name="Dallas_2010">{{cite journal | last1 = Dallas | first1 = SL | last2 = Bonewald | first2 = L | year = 2010 | title = Dynamics of the Transition from Osteoblast to Osteocyte | journal = Ann N Y Acad Sci | volume = 1192 | issue = 1 | pages = 437–443 | doi=10.1111/j.1749-6632.2009.05246.x| pmid = 20392270 | pmc = 2981593 | bibcode = 2010NYASA1192..437D }}</ref> Oxygen tension may regulate the differentiation of osteoblasts into osteocytes, and osteocyte hypoxia may play a role in disuse-mediated bone resorption.<ref name="Dallas_2010"/>

==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.<ref name="Noble_2008"/> They are the most common cell type in bone (31,900 per cubic millimeter in bovine bone to 93,200 per cubic millimeter in rat bone).<ref name="Noble_2008"/> Most of the receptor activities that play an important role in bone function are present in the mature osteocyte.<ref name="Noble_2008"/>

Osteocytes are an important regulator of bone mass.<ref name="Dance"/><ref name="Robling"/> Osteocytes contain glutamate transporters that produce nerve growth factors after bone fracture, evidence of a sensing and information transfer system.<ref name="Noble_2008"/> 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.<ref name="Noble_2008"/>

Osteocytes are mechanosensor cells that control the activity of osteoblasts and osteoclasts<ref name="Robling"/> within a basic multicellular unit (BMU), a temporary anatomic structure where bone remodeling occurs.<ref name="Bezooijen_2005">{{cite journal | last1 = ran Bezooijen Rl | first1 = Ran | last2 = Papapoulos | first2 = SE | last3 = Hamdy | first3 = NA | last4 = ten Dijke | first4 = P | last5 = Lowik | first5 = C | year = 2005 | title = Control of Bone Formation by Osteocytes | journal = BoneKEy-Osteovision | volume = 2 | issue = 12| pages = 33–38 }}</ref> Osteocytes generate an inhibitory signal that is passed through their cell processes to osteoblasts for recruitment to enable bone formation.<ref>{{cite journal | last1 = Marotti | first1 = G | last2 = Ferretti | first2 = M | last3 = Muglia | first3 = MA | last4 = Palumbo | first4 = C | last5 = Palazzani | first5 = SA | year = 1992 | title = A quantitative evaluation of osteoblast-osteocyte relationships on growing endosteal surface of rabbit tibiae | journal = Bone | volume = 13 | issue = 5| pages = 363–368 | doi=10.1016/8756-3282(92)90452-3| pmid = 1419377 | hdl = 11380/1322246 | hdl-access = free }}</ref>

Osteocytes are also a key endocrine regulator in the metabolism of minerals such as phosphates.<ref name="Dance"/> 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.<ref name="Bonewald_2011"/><ref name="Robling"/> Osteocyte regulation can be linked to disease. For example, Lynda Bonewald determined that osteocytes make FGF23, which travels through the bloodstream to trigger the release of phosphorus by the kidneys. Without enough phosphorus bones and teeth soften, and muscles become weak, as in X-linked hypophosphatemia.<ref name="Dance">{{cite journal |last1=Dance |first1=Amber |title=Fun facts about bones: More than just scaffolding |journal=Knowable Magazine |date=23 February 2022 |doi=10.1146/knowable-022222-1|doi-access=free |url=https://knowablemagazine.org/article/health-disease/2022/fun-facts-about-bones-more-just-scaffolding |access-date=8 March 2022|url-access=subscription }}</ref><ref>{{cite web |title=Soft and weak bones? Have you heard of X-linked hypophosphatemia (XLH)? Learn more about this disease and its symptoms. |url=https://www.xlhlink.com/pat/what-is-xlh/?gclid=CjwKCAiAo4OQBhBBEiwA5KWu__OicsW6-wTRSmfU4-35nu3O6cZcU7yy-QSOyrPLJ4mB25ilDRj-aRoC240QAvD_BwE |website=XLHLink |access-date=9 March 2022}}</ref><ref name="Robling">{{cite journal |last1=Robling |first1=Alexander G. |last2=Bonewald |first2=Lynda F. |title=The Osteocyte: New Insights |journal=Annual Review of Physiology |date=10 February 2020 |volume=82 |issue=1 |pages=485–506 |doi=10.1146/annurev-physiol-021119-034332 |pmid=32040934 |pmc=8274561 |hdl=1805/30982 |issn=0066-4278}}</ref><ref name="Dallas_2010"/>

===Sclerostin=== Osteocytes synthesize sclerostin, a secreted protein that inhibits bone formation by binding to LRP5/LRP6 coreceptors and blunting Wnt signaling.<ref name="Robling"/><ref name="Pajevic_2009"/> 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.<ref name="Bellido_2007">{{cite journal | last1 = Bellido | first1 = T | year = 2007 | title = Osteocyte Apoptosis Induces Bone Resorption and Impairs the Skeletal Response to Weighlessness | journal = BoneKEy-Osteovision | volume = 4 | issue = 9| pages = 252–256 | doi=10.1138/20070272}}</ref> Only osteocytes express sclerostin, which acts in a paracrine fashion to inhibit bone formation.<ref name="Bellido_2007"/> Sclerostin is inhibited by parathyroid hormone (PTH) and mechanical loading.<ref name="Bellido_2007"/> Sclerostin antagonizes the activity of BMP (bone morphogenetic protein), a cytokine that induces bone and cartilage formation.<ref name="Bezooijen_2005"/>

==Pathophysiology== Osteonecrosis refers to the classic pattern of cell death and complex osteogenesis and bone resorption processes. Osteocyte necrosis (ON) initiates with hematopoietic and adipocytic cellular necrosis along with interstitial marrow edema. ON happens after about 2 to 3 hours of anoxia; histological signs of osteocytic necrosis do not display until about 24 to 72 hours after hypoxia. ON is first characterized by pyknosis of nuclei, followed by hollow osteocyte lacunae. Capillary revascularization and reactive hyperemia slightly take place at the periphery of the necrosis site, followed by a repair process combining both bone resorption and production that incompletely changes dead with living bone. Nouveau bone overlays onto dead trabeculae along with fragmentary resorption of dead bone. Bone resorption outperforms formation resulting in a net removal of bone, deformed structural integrity of the subchondral trabeculae, joint incongruity, and subchondral fracture.<ref>{{Citation|last1=Nahian|first1=Ahmed|title=Histology, Osteocytes|date=2021|url=https://www.ncbi.nlm.nih.gov/books/NBK558990/|work=StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=32644416|access-date=2021-06-24|last2=AlEssa|first2=Ahmed M.}}</ref>

==Clinical significance== Clinically important research of gel based ''in vitro'' 3D model for the osteocytic potentiality of human CD34+ stem cells has been described. The results confirm that the human CD34+ stem cells possess unique osteogenic differentiation potential and can be used in the early regeneration of injured bone.<ref>{{Cite journal|last1=Srikanth|first1=Lokanathan|last2=Sunitha|first2=Manne Mudhu|last3=Kumar|first3=Pasupuleti Santhosh|last4=Chandrasekhar|first4=Chodimella|last5=Vengamma|first5=Bhuma|last6=Sarma|first6=Potukuchi Venkata Gurunadha Krishna|date=November 2016|title=Gel based in vitro 3D model exploring the osteocytic potentiality of human CD34+ stem cells|journal=Molecular Biology Reports|volume=43|issue=11|pages=1233–1242|doi=10.1007/s11033-016-4053-4|issn=1573-4978|pmid=27497820|s2cid=13230517}}</ref> Osteocytes die as a consequence of senescence, degeneration/necrosis, apoptosis (programmed cell death), and/or osteoclastic engulfment.<ref name="Tate_2004"/> The percentage of dead osteocytes in bone increases with age from less than 1% at birth to 75% after age 80.<ref>{{cite journal | last1 = Tomkinson | first1 = A | last2 = Reeve | first2 = J | last3 = Shaw | first3 = RW | last4 = Noble | first4 = BS | year = 1997 | title = The death of osteocytes via apoptosis accompanies estrogen withdrawal in human bone | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 9| pages = 3128–3135 | doi = 10.1210/jcem.82.9.4200 | pmid = 9284757 | doi-access = free }}</ref> Osteocyte apoptosis is thought to be related to decreased mechanotransduction, which possibly leads to the development of osteoporosis.<ref name="Heino_2009">{{cite journal | last1 = Heino | first1 = TJ | last2 = Kurata | first2 = K | last3 = Higaki | first3 = H | last4 = Vaananen | first4 = K | year = 2009 | title = Evidence of the role of osteocytes in the initiation of targeted remodeling | journal = Technology and Health Care | volume = 17 | issue = 1 | pages = 49–56 | doi = 10.3233/THC-2009-0534 | pmid = 19478405 }}</ref> Apoptotic osteocytes release apoptotic bodies expressing RANKL to recruit osteoclasts.<ref name="Bonewald_2011"/>

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.<ref name="Heino_2009"/> Skeletal unloading has been shown to induce osteocyte hypoxia ''in vivo'', this is when osteocytes undergo apoptosis and recruit osteoclasts to resorb bone.<ref name="Heino_2009"/> 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.<ref name="Heino_2009"/> 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.<ref name="Heino_2009"/>

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.<ref>{{cite journal | last1 = Burra | first1 = S | last2 = Nicolella | first2 = DP | last3 = Jiang | first3 = JX | year = 2011 | title = Dark horse in osteocyte biology | journal = Communicative and Integrative Biology | volume = 4 | issue = 1| pages = 48–50 | doi=10.4161/cib.13646| pmc = 3073269 | pmid=21509177}}</ref> 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.<ref name="Bonewald_2011"/><ref>{{cite journal | last1 = Carpentier | first1 = VT | last2 = Wong | first2 = J | last3 = Yeap | first3 = Y | last4 = Gan | first4 = C | last5 = Sutton-Smith | first5 = P | last6 = Badiei | first6 = A | last7 = Fazzalari | first7 = NL | last8 = Kuliwaba | first8 = JS | year = 2012 | title = Increased proportion of hypermineralized osteocyte lacunae in osteoporotic and osteoarthritic human trabecular bone: Implications for bone remodeling | journal = Bone | volume = 50 | issue = 3| pages = 688–694 | doi=10.1016/j.bone.2011.11.021 | pmid=22173055}}</ref> 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.<ref name="Bonewald_2011"/> It is now recognized that osteocytes respond in a variety of ways to the presence of implant biomaterials.<ref>{{cite journal |last1=Shah |first1=F.A. |last2=Thomsen |first2=P. |last3=Palmquist |first3=A. |title=A Review of the Impact of Implant Biomaterials on Osteocytes |journal=Journal of Dental Research |date=4 June 2018 |volume=97 |issue=9 |pages=977–986 |doi=10.1177/0022034518778033 |pmid=29863948|pmc=6055115 }}</ref>

== References == {{Reflist}}

== External links == {{Commons category}}

* {{BUHistology|02003loa}} – "Cartilage and Bone and Bone Histogenesis: cells of* {{BUHistology|02705loa}} – "Cartilage and Bone and Bone Histogenesis: compact bone"* =D [https://web.archive.org/web/20061212101008/http://casweb.cas.ou.edu/pbell/Histology/Captions/Bone/osteocyte.2.html Histology at ou.edu]

Category:Skeletal system Category:Secretory cells Category:Human cells