Bone Development and Ossification

The process of bone formation is called ossification. The 2 types of ossification are intramembranous ossification, in which bone is developed directly from mesenchyme cells, and endochondral ossification, in which a hyaline cartilage model is created 1st and then later replaced with bone. Bone continues to grow into early adulthood at the epiphyseal plates, where chondrocytes continue to divide, die, and be replaced with mineralized bone. Bone mineralization occurs because the osteoblasts allow high levels of calcium and phosphate to accumulate above critical threshold levels within bone.

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Overview of Bone Development

Definitions

The formation of bone is called ossification or osteogenesis.

Types of ossification

The 2 primary types of ossification are:

  • Endochondral ossification: a hyaline cartilage model is created from mesenchyme, then replaced with bone 
  • Intramembranous ossification: bones develop directly from mesenchyme

Review of bone structure

The 2 primary types of bone are compact bone and spongy bone.

  • Compact bone: 
    • Hard, dense outer layer of bones
    • Arranged in functional units known as osteons: a central canal containing nerves and vessels surrounded by concentric rings of calcified bone matrix and osteocytes
  • Spongy bone: 
    • Inner layer consisting of a lattice of thin pieces of osseous tissue called trabeculae
    • Found at the ends of long bones and in the middle of flat, short, and irregular bones

Related videos

Endochondral Ossification

Overview of endochondral ossification

  • Bones formed via endochondral ossification: all bones below the skull except for the clavicles
  • Hyaline cartilage is used as a template for bone formation. 
  • Process overview:
    • Chondrocytes create a hyaline cartilage model of the bone.
    • Chondrocytes within the model mature and hypertrophy → allows mineralization
    • Mineralization → ↓ chondrocyte nutrition → chondrocye death
    • Chondrocyte death creates space within the bone called lacunae.
    • Lacunae are invaded by vessels carrying osteoblasts, which lay down new bone.
    • New bone is remodeled into mature bone.

Detailed process of endochondral ossification

  • Mesenchyme differentiates into chondroblasts.
  • Chondroblasts secrete a hyaline cartilage matrix:
    • Forms a model of the bone
    • Model surrounded by membrane called perichondrium
    • Chondroblasts trapped within the matrix become chondrocytes.
  • Formation of the primary ossification center:
    • Occurs in the diaphysis (shaft) of long bones
    • Chondrocytes near the center of the model mature and hypertrophy.
    • Hypertrophied chondrocytes alter matrix contents (add collagen X and fibronectin) → allows mineralization to begin
  • Matrix mineralization:
    • Leads to ↓ nutrient delivery to chondrocytes → chondrocyte apoptosis 
    • Holes (called lacunae) develop in the matrix where chondrocytes used to exist 
  • Invasion of blood vessels:
    • Vascular buds (called periosteal buds) arise from the perichondrium
    • Grow toward the lacunae in the primary ossification center (center of diaphysis) 
    • Carry osteogenic cells with them into the lacunae:
      • Osteoblasts form new bone.
      • Osteoclasts break down bone and matrix.
    • Invading periosteal buds break down walls between lacunae, creating the primary marrow space (which will eventually become the medullary cavity).
  • Seeding of osteogenic cells:
    • Periosteal buds deposit osteoblasts into the marrow space.
    • At the same time, perichondrium ossifies into a bony collar surrounding the forming bone → now known as periosteum
  • Osteoblasts create woven bone:
    • Osteoblasts now lining the marrow spaces lay down osteoid tissue (organic components of bone matrix) and calcify it → called woven bone
    • Bone remodeling (via osteoclasts and osteoblasts) replaces woven bone with mature trabecular (spongy) bone
  • Growth in bone length:
    • Cartilage continues dividing at the epiphyses → ↑ bone length
    • Area is known as the epiphyseal plates (i.e., growth plates).
    • Continues providing longitudinal growth into early adulthood
  • Secondary ossification centers:
    • Located within the epiphyses
    • Appear around the time of birth
    • Follow the same pattern as the primary ossification center:
      • Matrix mineralization
      • Chondrocyte death → creation of lacunae
      • Invasion of blood vessels
      • Seeding of the lacunae with osteoblasts, which create bone
  • After birth, cartilage remains at:
    • Articular surfaces
    • Epiphyseal plates: 
      • Also known as growth plates
      • Ossify after puberty (resulting in no further longitudinal growth)
Process of endochondral ossification

Process of endochondral ossification

Image: “Process of endochondral ossification” by CNX OpenStax. License: CC BY 4.0

Intramembranous Ossification

Intramembranous ossification is a direct conversion of mesenchymal cells into osseous tissue.

Bones formed via intramembranous ossification

These bones have a middle layer of spongy bone sandwiched between layers of compact bone:

  • Flat bones of the skull
  • Facial bones
  • Mandible
  • Clavicle
Structure of a flat bone

Structure of a flat bone

Image: “This cross-section of a flat bone shows the spongy bone (diploë) lined on either side by a layer of compact bone” by OpenStax College. License: CC BY 4.0

Process

  • Mesenchymal cells condense into sheets and differentiate into:
    • Osteogenic cells → further differentiate into osteoblasts
    • Capillaries
  • Between mesenchymal sheets:
    • Osteogenic cells/osteoblasts condense into ossification centers 
    • Osteoblasts begin secreting osteoid: soft collagenous bone matrix (soft trabeculae)
    • Trabeculae grow → osteoblasts deposit calcium phosphate onto the matrix
  • Osteoblasts trapped within the mineralizing matrix transform into osteocytes
  • Mineralized trabeculae:
    • Middle portion: becomes permanent spongy bone (middle layer of flat bones)
    • Surface portions: 
      • Continue calcifying until all the spaces are filled in → compact bone
      • Remodeling occurs via osteoclasts and osteoblasts to form lamellar bone.
  • Surface mesenchyme:
    • Remains uncalcified
    • Becomes more and more fibrous
    • Eventually differentiates into periosteum
Intramembraneous_Ossification

Process of intramembranous ossification

Image: “Intramembranous ossification follows four steps. (a) Mesenchymal cells group into clusters, and ossification centers form. (b) Secreted osteoid traps osteoblasts, which then become osteocytes. (c) Trabecular matrix and periosteum form. (d) Compact bone develops superficial to the trabecular bone, and crowded blood vessels condense into red marrow.” by OpenStax College. License: CC BY 4.0

Bone Growth and Mineralization

Bone growth

The epiphyseal plates are found in the metaphysis of long bones, the transitional region between the diaphysis (shaft) and epiphysis (ends). There are 5 distinct histologic zones:

  1. Zone of reserve cartilage: 
    • Located farthest from the marrow
    • Consists of resting cartilage
    • The chondrocytes disappear after puberty → “closing” the growth plates
  2. Zone of proliferation: 
    • Chondrocytes arrange themselves in columns and divide.
    • Leads to longitudinal growth
  3. Zone of hypertrophy: 
    • Chondrocytes hypertrophy, mature, and transform (just as in endochondral ossification).
    • Allows for mineralization and additional longitudinal growth
  4. Zone of calcification: Matrix is mineralized. 
  5. Zone of resorption and bone deposition: 
    • Chondrocytes die, creating longitudinal channels that are invaded by vessels carrying osteogenic cells.
    • Osteoclasts dissolve the calcified cartilage.
    • Osteoblasts line the channel walls and lay down concentric lamellae of matrix until only a narrow channel remains → the central channel of a mature osteon
Histologic zones of the epiphyseal plates

Histologic zones of the epiphyseal plates

Image by Lecturio.

Bone mineralization

  • Calcium (Ca2+) and phosphate (PO43–) combine to form hydroxyapatite crystals on the bone matrix.
  • Crystals can form only when certain threshold levels for Ca2+ and PO43– are exceeded:
    • Most tissues have inhibitors preventing this from happening.
    • Bone-forming cells secrete osteocalcin, which binds extracellular Ca2+ → allows Ca2+ to accumulate
  • Osteoblasts respond to ↑ Ca2+ by secreting alkaline phosphatase, which ↑ PO43– ions.
  • At ↑ levels, calcium and phosphate crystallize into hydroxyapatite crystals (Ca10(PO4)6OH2) on the organic matrix.

Clinical Relevance

  • Achondroplasia: autosomal dominant condition caused by mutations in the FGFR3 gene, which inhibits chondrocyte proliferation, impairing endochondral bone formation. Clinically, achondroplasia presents in infants with short stature, shortening of the limbs, characteristic facies, abnormalities in the spinal curvature, and slow motor development. Intellectual development is normal. Management is aimed at optimizing functional capacity and treating complications, such as recurrent ear infections, sleep apnea, leg bowing, and spinal stenosis.
  • Osteogenesis imperfecta: also known as “brittle bone disease.” Osteogenesis imperfecta is a rare genetic connective tissue disorder characterized by severe bone fragility. Although it is considered a single disease, it includes over 16 genotypes, with the most common types causing mutations in type 1 collagen. Some forms are lethal in utero. There is no definitive cure; treatment is supportive, usually involving bisphosphonates, and is focused on reducing pain, fracture frequency, and bone deformity and increasing ambulation. 
  • Rickets: disorder of decreased bone mineralization in children. In rickets, the hypertrophic chondrocytes in the epiphyseal growth plates fail to undergo apoptosis. This failure results in insufficient mineralization of the cartilage and is most commonly due to a deficiency in vitamin D, the vitamin that promotes bone mineralization. Rickets presents with skeletal deformities, including bowed legs, and growth abnormalities.  Treatment includes vitamin D, calcium, and phosphorus supplementation.
Rickets

Rickets

Image: “X-rays of both lower limbs showing severe bowing of the legs and diffuse osteopenia. It also shows dense transverse lines in the tibia suggestive of looser’s zones indicative of rickets” by Al-Sharafi BA et al. License: CC BY 4.0

References

  1. Saladin, K.S., Miller, L. (2004). Anatomy and physiology, 3rd ed. pp. 218–224. McGraw Hill Education.
  2. Manolagas, S.C. (2020). Normal skeletal development and regulation of bone formation and resorption. UpToDate. Retrieved August 4, 2021, from https://www.uptodate.com/contents/normal-skeletal-development-and-regulation-of-bone-formation-and-resorption 
  3. Breeland, G. (2021). Embryology, bone ossification. StatPearls. Retrieved August 6, 2021, from https://www.statpearls.com/articlelibrary/viewarticle/36128/ 
  4. OpenStax College, Anatomy and Physiology. OpenStax CNX. Retrieved August 5, 2021, from https://philschatz.com/anatomy-book/contents/m46301.html 

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