Most bones in your body did not begin as bone. They began as a soft cartilage model shaped like the bone they would become, and that model was later rebuilt as bone. Endochondral ossification is the name for that rebuilding, cartilage first and then bone. The process does not stop at birth: it is what makes children grow taller, and the body runs it again to mend a broken bone.1PubMed. Expression of cathepsins B, H, K, L, and S and matrix metalloproteinases 9 and 13 during chondrocyte hypertrophy and endochondral ossification in mouse fracture callus
The Steps of Endochondral Ossification
It starts in the early embryo, where loosely packed cells in a budding limb crowd together into a dense clump at the spot where a bone will be. Cells in the clump become cartilage-making cells. Cartilage is the smooth, flexible tissue you can feel at the tip of your nose or ear. A ring of surrounding cells forms the outer sleeve of the future bone.2PubMed Central. Hes1 marks peri-condensation mesenchymal cells that generate both chondrocytes and perichondrial cells in early bone development A single master switch gene is needed for this step; when it is shut off in early limbs, neither cartilage nor bone forms at all.3PubMed Central. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6
Inside the model, the cartilage cells first divide rapidly and line up in stacks, which lengthens it. Then they stop dividing and swell to many times their size.4International Journal of Oral Science. The role of vascular endothelial growth factor in ossification Swollen cartilage cells switch on genes that break down their surroundings and invite blood vessels in.5Acta Naturae. Changes in Gene Expression Associated with Matrix Turnover, Chondrocyte Proliferation and Hypertrophy in the Bovine Growth Plate The space around them then hardens with minerals, the first step toward bone.6PubMed. The role of the growth plate in longitudinal bone growth
The ring of cells around the model forms a thin sleeve of bone early on, so the shaft is wrapped in bone while the cartilage inside is still being replaced. The first conversion happens in the middle of the shaft. From there, conversion spreads toward both ends. Later, separate conversion sites open inside the ends of the bone, and the cartilage left between shaft and ends becomes the growth plate. The shaft of a long bone converts first, from around the fifth to eighth week of embryonic life onward. The ends convert later, often after birth, which leaves cartilage between the shaft and the ends. That is why much of a baby’s skeleton is still partly cartilage at birth.
The swollen cells release a signal that draws blood vessels into the hardened cartilage.7International Journal of Oral Science. The role of vascular endothelial growth factor in ossification When that signal was blocked in young mice, vessels barely entered, the swollen cartilage piled up, and spongy bone failed to form.8PubMed. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation Once the vessels push into the middle of the model, they bring cells that chew away the cartilage and cells that lay down bone.9PubMed. Endochondral ossification in fracture callus during long bone repair: the localisation of ‘cavity-lining cells’ within the cartilage The clearing leaves a hollow, spongy framework of leftover mineralized cartilage. Bone-building cells coat that framework, and the hollow spaces fill with marrow.
Cartilage does not simply harden into bone like drying cement. It is removed, and new bone tissue is built in its place. Older textbooks said all the swollen cartilage cells die, but many don’t: they can turn into bone-building cells and bone marrow cells themselves.10eLife. Hypertrophic chondrocytes serve as a reservoir for marrow-associated skeletal stem and progenitor cells, osteoblasts, and adipocytes during skeletal development
How Growth Plates Make Bones Longer
The growth plate is a thin disc of cartilage near each end of a long bone, and it is the main site where long bones lengthen.11PubMed. The role of the growth plate in longitudinal bone growth Cartilage forms there through cell multiplication and swelling, then hardens, is broken down, and is replaced by bone.12PubMed. The role of the growth plate in longitudinal bone growth A second bone-forming site inside each bone end splits off the joint cartilage from the growth plate and helps hold the plate’s structure.13eLife. Secondary ossification center induces and protects growth plate structure
The plate is organized in layers that match the steps above:
- Resting layer: a reserve of quiet cartilage cells that feed the plate.
- Dividing layer: cells multiply and stack into columns.
- Swelling layer: cells enlarge and the surrounding cartilage hardens.
- Bone layer: blood vessels and bone cells replace the cartilage, adding to the shaft.
The dividing layer keeps adding new cells on the side nearest the joint, while the layer nearest the shaft is converted to bone. New cartilage is made on one side at about the pace it is replaced on the other, so the plate is not used up quickly. The shaft gains length as the replaced cartilage is left behind, and the plate is carried away from the middle of the bone. It stays about the same thickness all through childhood while the bone behind it grows longer.
Near the end of puberty, the cartilage is used up and replaced entirely by bone. This is closure. After it, bones can no longer grow in length, so height stops increasing. On X-rays, open plates show as dark lines near the bone ends, which doctors use to judge bone age. Timing differs between people and is typically earlier in girls than in boys.
Growth plate injuries in children get special attention because the plate is softer than the surrounding bone. Damage can disturb the layered process and slow growth in that bone, so doctors watch such fractures over time to check that the limb grows evenly.
How It Differs From Direct Bone Formation
Some bones, such as the flat bones of the skull and most of the collarbone, form directly from cells without any cartilage. This route is called intramembranous ossification. Arm and leg bones, the spine, ribs and pelvis are built through a cartilage model first. Even the first mineral crystals differ: clusters formed via cartilage are more than ten times larger than those formed directly.14PubMed. Distinct Morphologies of Bone Apatite Clusters in Endochondral and Intramembranous Ossification The two routes start crystals in different tiny structures, small bubbles in direct bone and fragments of cartilage cell membranes in cartilage-first bone.15PubMed. Distinct Morphologies of Bone Apatite Clusters in Endochondral and Intramembranous Ossification
A cartilage model suits weight-bearing long bones because cartilage can grow quickly from inside, while bone can only add to its surfaces. That lets a bone lengthen throughout childhood.
A baby’s skull shows the other route. The soft spots on a baby’s head are gaps between plates formed by direct bone formation, and these plates grow at their edges rather than from a growth plate.
The sorting is not perfectly tidy. Most of the skull’s flat roof bones form directly, but the base of the skull forms with a cartilage model first, so a single skull mixes both routes. The collarbone is a mixed case, with most of it formed directly and its ends adding cartilage-based growth.
What Controls the Pace
A local feedback loop works a bit like a thermostat. Swelling cartilage cells release a signal called Indian hedgehog that prompts nearby cells to make a second signal, PTHrP.16PubMed. The parathyroid hormone-related protein and Indian hedgehog feedback loop in the growth plate PTHrP keeps cartilage cells dividing and holds off their swelling, which in turn cuts back the hedgehog signal.17PubMed. The parathyroid hormone-related protein and Indian hedgehog feedback loop in the growth plate The two signals balance each other and set the pace of the whole growth plate.18PubMed. The parathyroid hormone-related protein and Indian hedgehog feedback loop in the growth plate Mice lacking PTHrP switch to swelling too early and turn cartilage to bone prematurely.19PubMed Central. Growth Plate Chondrocytes: Skeletal Development, Growth and Beyond
Within one plate, cells near the top divide and make PTHrP, which keeps cells in the dividing state. As cells are pushed away from the source of PTHrP, they stop receiving that signal and begin to swell. Swelling cells make Indian hedgehog, which tells cells near the top to produce more PTHrP, so the loop corrects itself. The distance between the top of the plate and the swelling zone stays steady, which keeps the plate organized as it works.
Hormones and movement also matter. Thyroid hormone pushes cartilage cells from dividing to swelling.20PubMed Central. The growth plate: a physiologic overview It works by adjusting several growth signals, including IGF-1, PTHrP and Indian hedgehog.21PubMed Central. Role and Mechanisms of Actions of Thyroid Hormone on the Skeletal Development Mechanical loading from movement and weight also influences how growth plate cells multiply and mature.22PubMed. The effect of mechanical loading on the metabolism of growth plate chondrocytes
This helps explain some growth problems. An underactive thyroid in childhood can slow bone growth and delay bone age. Growth hormone acts largely through IGF-1, one of the same signals. That is why doctors check thyroid and growth hormone when a child grows unusually slowly.
When Endochondral Ossification Goes Wrong
Achondroplasia, the most common form of dwarfism, is caused by a change in the FGFR3 gene that leaves its signal switched on too strongly. The overactive signal slows cartilage cell division in growth plates.23PubMed Central. Advances in the mechanism and therapies of achondroplasia It does so by raising levels of proteins that brake the cell cycle.24PubMed Central. Advances in the mechanism and therapies of achondroplasia It also disrupts the reserve layer of the plate, which normally supplies new cartilage cells.25PubMed Central. Excess FGFR3 signaling in achondroplasia disrupts turnover of resting zone chondrocytes via CREB signaling The long bones stay short, while the top of the skull, which forms directly without cartilage, is affected less.
Arms and legs lengthen mostly through growth plates, so a slowed plate shortens them noticeably, especially the upper arm and thigh. The torso is of near-typical length. The base of the skull grows through cartilage, so the middle of the face can be affected too.
One approved medicine, vosoritide, counters the overactive FGFR3 signal. It is given to children with open growth plates, because it works only while the plate is still active and responsive.
Bone can also form in the wrong place. Heterotopic ossification is bone forming in muscle or other soft tissue, through cartilage first and then bone.26Japanese Dental Science Review. The pathophysiology of heterotopic ossification: Current treatment considerations in dentistry It can be triggered by major surgery, large wounds, burns, and other conditions.27Japanese Dental Science Review. The pathophysiology of heterotopic ossification: Current treatment considerations in dentistry
For a patient, it often follows hip replacement, severe burns, or spinal cord injury. Signs can include pain, swelling, and stiffness or lost movement near a joint, and X-rays show bone where none should be. Treatments in use include medicines and radiation to prevent it after high-risk surgery.
How Broken Bones Heal the Same Way
Fracture repair repeats in adults the same steps the skeleton used during growth.28PubMed. Expression of cathepsins B, H, K, L, and S and matrix metalloproteinases 9 and 13 during chondrocyte hypertrophy and endochondral ossification in mouse fracture callus A healing break first forms a soft callus, a cartilage bridge across the gap.29PubMed. Endochondral ossification in fracture callus during long bone repair: the localisation of ‘cavity-lining cells’ within the cartilage Blood vessels then grow into the callus and drive the replacement of cartilage with bone.30PubMed. Endochondral ossification in fracture callus during long bone repair: the localisation of ‘cavity-lining cells’ within the cartilage Some cartilage cells in the callus turn directly into bone-forming cells.31PubMed. A new role for the chondrocyte in fracture repair: endochondral ossification includes direct bone formation by former chondrocytes
The break tears blood vessels, so the gap is first filled with a clot and the area has little oxygen. Cartilage tolerates low oxygen and can form in a poorly supplied gap, which is why the soft callus appears first. Once new vessels grow in, oxygen reaches the area and bone-building cells can replace the cartilage. The callus is a temporary bridge until the blood supply catches up.
In the first days there is swelling and a blood clot at the break. Over the next couple of weeks the callus forms, then turns to hard bone that shows on X-ray. Remodeling continues for months.
That is why a cast matters. Too much motion can keep the callus as cartilage or fibrous tissue. The vessel step needs blood supply, so smoking and poor circulation slow healing. Following weight-bearing advice protects the callus while it converts.
Researchers use the same logic to repair large defects: labs grow a cartilage model first, then implant it so it becomes bone. This approach helps build bone with its own blood supply, though it is still mostly experimental.
Where This Way of Building Bone Came From
Endochondral ossification is the younger of the two routes; older bony armor in skin formed directly.32PubMed Central. Where did bone come from? Early armored fishes had bony plates in the skin with no cartilage stage. The same cell types and genes were later put to use inside the skeleton, so the newer route reuses older tools. It evolved gradually, starting with bone laid on the outside of cartilage before cartilage was replaced inside.33PubMed Central. Where did bone come from?
Sharks have mostly cartilage skeletons.34PubMed. Endochondral bone in an Early Devonian ‘placoderm’ from Mongolia Yet an ancient fish fossil with extensive cartilage-replacing bone suggests shark ancestors lost this bone rather than never having it.35PubMed. Endochondral bone in an Early Devonian ‘placoderm’ from Mongolia