Editing Endochondral ossification

{{short description|Cartilaginous bone development that forms the long bones}}
{{Infobox anatomy
| Name        = Endochondral ossification
| Latin       =
| Image       = SOC001.jpg 
| Caption     = A schematic representation of endochondral ossification.
| Image2      =
| Caption2    =
| Width       = 300
| System      =
| Precursor   =
}}

'''Endochondral ossification'''<ref>Etymology from {{langx|el|ἔνδον}}/''endon'', "within", and χόνδρος/''chondros'', "cartilage"</ref><ref>{{cite web
| url       = http://www.myetymology.com/english/endochondral.html
| archive-url = https://web.archive.org/web/20110714142832/http://www.myetymology.com/english/endochondral.html
| url-status = usurped
| archive-date = July 14, 2011
| title     = Etymology of the English word endochondral
| publisher = myEtymology | access-date =
}}</ref> is one of the two essential pathways by which [[bone tissue]] is produced during [[fetal development]] and [[bone healing|bone repair]] of the [[mammal]]ian [[skeleton|skeletal system]], the other pathway being [[intramembranous ossification]]. Both endochondral and intramembranous processes initiate from a precursor [[mesenchymal cells|mesenchymal tissue]], but their transformations into bone are different. In intramembranous ossification, mesenchymal tissue is directly converted into bone. On the other hand, endochondral ossification starts with mesenchymal tissue turning into an intermediate [[hyaline cartilage|cartilage stage]], which is eventually substituted by bone.<ref name=brief>{{cite journal |last1=Šromová |first1=V |last2=Sobola |first2=D |last3=Kaspar |first3=P |title=A Brief Review of Bone Cell Function and Importance. |journal=Cells |date=5 November 2023 |volume=12 |issue=21 |page=2576 |doi=10.3390/cells12212576 |doi-access=free |pmid=37947654 |pmc=10648520}}{{CC-notice|cc=by4}}</ref>

Endochondral ossification is responsible for development of most bones including [[long bone|long]] and [[short bone|short]] bones,<ref>{{Citation|last1=Cowan|first1=PT|title=Anatomy, Bones|date=2023|url=https://www.ncbi.nlm.nih.gov/books/NBK537199//|work=StatPearls|place=Treasure Island, Florida (FL)|publisher=StatPearls Publishing|pmid=30725884|last2=Kahai|first2=P}}</ref> the bones of the [[axial skeleton|axial]] ([[ribs]] and [[vertebrae]]) and the [[appendicular skeleton|appendicular]] skeleton (e.g. [[upper limb|upper]] and [[lower limb|lower]] limbs),<ref name=Elsevier>{{cite journal |last1=Blumer |first1=Michael J. F. |title=Bone tissue and histological and molecular events during development of the long bones |journal=Annals of Anatomy - Anatomischer Anzeiger |date=1 May 2021 |volume=235 |pages=151704 |doi=10.1016/j.aanat.2021.151704 |pmid=33600952 |issn=0940-9602|doi-access=free}}</ref> the bones of the [[Base of skull|skull base]] (including the [[ethmoid bone|ethmoid]] and [[sphenoid bone|sphenoid]] bones)<ref name="Lang">{{cite book |last1=Sadler |first1=T.W. |title=Langman's medical embryology |date=2023 |publisher=Wolters Kluwer Health |isbn=978-1975179960 |edition=15th |url=https://shop.lww.com/Langman-s-Medical-Embryology/p/9781975179960}}</ref> and the medial end of the [[clavicle]].<ref>{{Citation|last1=Hyland|first1=S|last2=Charlick|first2=M|last3=Varacallo|first3=M|title=Anatomy, Shoulder and Upper Limb, Clavicle|date=2023|url=https://www.ncbi.nlm.nih.gov/books/NBK525990/|work=StatPearls|place=Treasure Island, Florida FL)|publisher=StatPearls Publishing|pmid=30252246}}</ref> In addition, endochondral ossification is not exclusively confined to embryonic development; it also plays a crucial role in the [[#Fracture healing|healing of fractures]].<ref name="brief" />

==Formation of the cartilage model==
The initiation of endochondral ossification starts by proliferation and condensation of [[mesenchymal cells]] in the area where the bone will eventually be formed. Subsequently, these mesenchymal progenitor cells differentiate into [[chondroblasts]], which actively synthesize cartilage matrix components. Thus, the initial hyaline cartilage template is formed, which has the same basic shape and outline as the future bone.<ref name=Paw>{{cite book |last1=Pawlina |first1=Wojciech |title=Histology: a text and atlas: with correlated cell and molecular biology |date=2024 |publisher=Wolters Kluwer |isbn=9781975181574 |edition=9th |url=https://www.lww.co.uk/9781975181574/histology-a-text-and-atlas/}}</ref>

{| class="wikitable"
|+ This hyaline cartilage template expands through both:<ref name="Paw" /><ref name="Jun">{{cite book |last1=Mescher |first1=Anthony L. |title=Junqueira's Basic Histology: Text and Atlas |date=2023 |publisher=McGraw-Hill Education |isbn=978-1264930395 |edition=17th |url=https://www.mhprofessional.com/junqueira-s-basic-histology-text-and-atlas-seventeenth-edition-9781264930395-usa |language=en}}</ref>
|-
!  !! Interstitial growth !! Appositional growth
|-
| Cellular protagonists || [[Chondrocytes]] present within the existing cartilage. || [[Chondroblasts]] that develop from the perichondrium.
|-
| Mechanism || Chondrocytes proliferate and lay down matrix. || Chondroblasts differentiate into chondrocytes and lay down matrix.
|-
| Site of expansion || From within. || From the external surface of existing cartilage.
|-
| Outcome || Increase in length. || Increase in width and thickness.
|}

==Primary center of ossification==
[[File:41413 2018 21 Fig1 HTML.jpg|upright=1.5|thumb|A schematic for [[long bone]] endochondral ossification.]]
In developing bones, ossification commences within the primary ossification center located in the center of the [[diaphysis]] (bone shaft),<ref name="Elsevier" /> where the following changes occur:

<ol type="a">
<li>The perichondrium surrounding the cartilage model transforms into the [[periosteum]]. During this transformation, special cells within the perichondrium switch gears. Instead of becoming cartilage cells ([[chondrocytes]]), they mature into bone-building [[osteoblasts]].<ref name="Elsevier" /> This newly formed bone can be called "periosteal bone" as it originates from the transformed periosteum. However, considering its developmental pathway, it could be classified as "intramembranous bone".<ref name="Paw" /></li>
<li>After the formation of the periosteum, chondrocytes in the primary center of ossification begin to grow ([[hypertrophy]]). They begin secreting:<ref name="Richard" /><ref name=Plastic>{{cite journal |last1=Chagin |first1=AS |last2=Chu |first2=TL |title=The Origin and Fate of Chondrocytes: Cell Plasticity in Physiological Setting. |journal=Current Osteoporosis Reports |date=December 2023 |volume=21 |issue=6 |pages=815–824 |doi=10.1007/s11914-023-00827-1 |pmid=37837512 |pmc=10724094}}</ref>{{bulleted list |[[Collagen]] type X, which causes stiffness and compression of the [[extracellular matrix]].| [[Matrix metalloproteinases]].| [[Vascular endothelial growth factor]] (VEGF), which controls forthcoming vascular invasion.|[[Alkaline phosphatase]], which causes calcification of the cartilage matrix. This calcification prevents passage of nutrients to chondrocytes leading to their death. }} 
<li>When chondrocytes die, matrix metalloproteinases result in catabolism of various components within the extracellular matrix and the physical boundaries between neighboring [[Lacuna (histology)|lacunae]] (the spaces housing chondrocytes) weaken. This can lead to the merging of these lacunae, creating larger empty spaces.<ref name="Paw" /><ref name="Jun" />
</li>
<li>Blood vessels arising from the periosteum invade these empty spaces and mesenchymal stem cells migrate guided by penetrating blood vessels. Following the invading blood vessels, mesenchymal stem cells reach these empty spaces and undergo differentiation into osteoprogenitor cells. These progenitors further mature into osteoblasts, that deposit unmineralized bone matrix, termed osteoid. Mineralization subsequently follows leading to formation of bone trabeculae (Endochondral bone formation).<ref name="Plastic" />
</ol>
[[File:Hypertrophic Zone of Epiphyseal Plate.jpg|thumb|[[Light micrograph]] of undecalcified [[epiphyseal plate]] showing endochondral ossification: healthy [[chondrocyte]]s (top) become degenerating ones (bottom), characteristically displaying a calcified [[extracellular matrix]].]]
==Secondary center of ossification==
During the postnatal life, a secondary ossification center appears in each end ([[epiphysis]]) of long bones. In these secondary centers, cartilage is converted to bone similarly to that occurring in a primary ossification center.<ref name="Paw" /> As the secondary ossification centers enlarge, residual cartilage persists in two distinct locations:<ref name="Plastic" />{{bulleted list |Articular cartilage: This layer coats the bone ends, concerned with [[joint]] movement. |[[epiphyseal plate|Epiphyseal growth plate]]: This transverse layer lies between the [[epiphysis]] and [[diaphysis]]. It’s composed of highly active chondrocytes and responsible for longitudinal bone growth. Consequently, the bone elongates at this growth plate until closure occurs at skeletal maturity. }}

At the end of an individual’s growth period, the production of new cartilage in the epiphyseal plate stops. After this point, existing cartilage within the plate turns into mature bone tissue.<ref name="Paw" />

==Histology==
[[File:Epiphyseal growth plate.jpg|thumb|Zones of endochondral ossification.]]
During endochondral ossification, five distinct zones can be seen at the light-microscope level:<ref name="brief" />
{| class="wikitable"
|-
!Name
!Definition
|-
|Zone of resting cartilage
| This zone contains normal, resting [[hyaline cartilage]].
|-
| Zone of proliferation / cell columns
| In this zone, [[chondrocyte]]s undergo rapid [[mitosis]], forming distinctive looking columns.
|-
| Zone of maturation / hypertrophy
| In this zone, the chondrocytes undergo [[hypertrophy]] (become enlarged). Chondrocytes contain large amounts of [[glycogen]] and begin to secrete [[vascular endothelial growth factor]] to initiate vascular invasion.
|-
|Zone of calcification
| In this zone, [[chondrocyte]]s are either dying or dead, leaving cavities that will later become invaded by bone-forming cells.  Chondrocytes here die when they can no longer receive nutrients or eliminate wastes via diffusion.  This is because the calcified matrix is much less hydrated than hyaline cartilage.
|-
|Zone of ossification
| Osteoprogenitor cells invade the area and differentiate into osteoblasts, which elaborate matrix that becomes calcified on the surface of calcified cartilage.
|}
[[File:Epi plate.jpg|upright=2]]

==Fracture healing==
For complete recovery of a [[bone fracture|fractured]] bone’s biomechanical functionality, the [[bone healing]] process needs to culminate in the formation of lamellar bone at the fracture site to withstand the same forces and stresses it did before the fracture. [[Bone healing#Secondary healing|Indirect fracture healing]], the most common type of bone repair,<ref name="Richard">{{cite journal|last1=Richard|first1=Marsell|last2=Thomas A|first2=Einhorn|title=The biology of fracture healing|journal=Injury|date=1 June 2012|volume=42|issue=6|pages=551–555|doi=10.1016/j.injury.2011.03.031|pmid=21489527|pmc=3105171}}</ref> relies heavily on endochondral ossification. In this type of healing, endochondral ossification occurs within the fracture gap and external to the periosteum. In contrast, intramembranous ossification takes place directly beneath the periosteum, adjacent to the broken bone’s ends.<ref name="Richard" /><ref>{{cite journal |last1=Bahney |first1=Chelsea S. |last2=Hu |first2=Diane P. |last3=Miclau |first3=Theodore |last4=Marcucio |first4=Ralph S. |title=The Multifaceted Role of the Vasculature in Endochondral Fracture Repair |journal=Frontiers in Endocrinology |date=5 February 2015 |volume=6 |pages=4 |doi=10.3389/fendo.2015.00004 |pmid=25699016 |issn=1664-2392 |pmc=4318416|doi-access=free}}</ref>
[[File:Endo Fracture.jpg|upright=1.5|thumb|A schematic of endochondral fracture, where '''B''' shows the location of both endochondral and intramembranous ossification.]]
==Additional images==
<gallery>
 File:Proximal tibia Masson Goldner Trikrom rabbit 600x growth zone.jpg|Masson Goldner trichrome stain of growth plate in a rabbit tibia.
 File:Gray79.png|Section of fetal bone of cat. ir. Irruption of the subperiosteal tissue. p. Fibrous layer of the periosteum. o. Layer of osteoblasts. im. Subperiosteal bony deposit.
 File:Endochondral CCN.jpg|Process of endochondral ossification.
 File:Gray80.png|Drawing of part of a longitudinal section of the developing femur of a rabbit. a. Flattened cartilage cells. b. Enlarged cartilage cells. c, d. Newly formed bone. e. Osteoblasts. f. Giant cells or osteoclasts. g, h. Shrunken cartilage cells.
</gallery>

==References==
{{Reflist}}

{{Bone and cartilage}}

[[Category:Animal developmental biology]]
[[Category:Skeletal system]]