Musculoskeletal System - Bone Development

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Endochondral bone

The mesoderm forms nearly all the connective tissues of the musculoskeletal system, except within the head where neural crest also contributes connective tissues. Each tissue (cartilage, bone, and muscle) goes through many different mechanisms of differentiation.

The 2 key developmental processes are the initial "patterning" of bone location and then the overt "differentiation" of bone through the process of ossification.

Bone is formed through a lengthy process involving ossification of a cartilage formed from mesenchyme. Two main forms of ossification occur in different bones, intramembranous (eg skull) and endochondrial (eg limb long bones) ossification. Ossification continues postnatally, through puberty until mid 20s. Early ossification occurs at the ends of long bones.

The two major parts of the human skeleton are the axial (80 bones in skull, vertebra, ribs, sternum) and appendicular (126 bones in limbs, shoulders, pelvis) skeletons.

Musculoskeletal and limb abnormalities are one of the largest groups of congenital abnormalities.

Musculoskeletal Links: Introduction | Mesoderm | Somitogenesis | Limb | Cartilage | Bone | Bone Timeline | Axial Skeleton | Skull | Joint | Muscle | Tendon | Diaphragm | Lecture - Musculoskeletal Development | Abnormalities | Limb Abnormalities | Cartilage Histology | Bone Histology | Skeletal Muscle Histology | Category:Musculoskeletal

Some Recent Findings

Historic images of the skull by Vesalius
More recent papers
Mark Hill.jpg
This table shows an automated computer PubMed search using the listed sub-heading term.
  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent

Search term: Bone Embryology

Gustavo Narvaes Guimarães, Thaisângela Lopes Rodrigues, Ana Paula de Souza, Sergio Roberto Line, Marcelo Rocha Marques Parathyroid Hormone (1-34) Modulates Odontoblast Proliferation and Apoptosis via PKA and PKC-Dependent Pathways. Calcif. Tissue Int.: 2014; PMID:25012507 Tohru Kimura, Yoshiaki Kaga, Hiroshi Ohta, Mika Odamoto, Yoichi Sekita, Kunpeng Li, Noriko Yamano, Keita Fujikawa, Ayako Isotani, Norihiko Sasaki, Masashi Toyoda, Katsuhiko Hayashi, Masaru Okabe, Takashi Shinohara, Mitinori Saitou, Toru Nakano Induction of Primordial Germ Cell-Like Cells from Mouse Embryonic Stem Cells by ERK Signal Inhibition. Stem Cells: 2014; PMID:24989326 Yuri Yamamoto, Yuri Yamamoto, Kenji Takada Wassmund osteotomy for excessive gingival display: a case report with three-dimensional facial evaluation. Aust Orthod J: 2014, 30(1);81-8 PMID:24968650 Faten Tinsa, Samia Hamouda, Manel Bellalah, Dorra Bousnina, Lotfi Karboul, Khadija Boussetta, Souad Bousnina Unusual feature of pycnodysostosis: pectus carinatum. Tunis Med: 2014, 92(2);180-1 PMID:24938251 Hong-Bin Zhao, She-Ning Qi, Ju-Zi Dong, Xiao-Qin Ha, Xiao-Yun Li, Quan-Wei Zhang, Yin-Shu Yang, Jie Bai, Ling Zhao Salidroside induces neuronal differentiation of mouse mesenchymal stem cells through Notch and BMP signaling pathways. Food Chem. Toxicol.: 2014; PMID:24929042

Adult Human Skeleton

Adult axial skeleton
Adult appendicular skeleton
Adult axial skeleton Adult appendicular skeleton


Fetal head (week 12)
  • The Developing Human: Clinically Oriented Embryology (8th Edition) by Keith L. Moore and T.V.N Persaud - Moore & Persaud Chapter 15 the skeletal system
  • Larsen’s Human Embryology by GC. Schoenwolf, SB. Bleyl, PR. Brauer and PH. Francis-West - Chapter 11 Limb Dev (bone not well covered in this textbook)
  • Before we Are Born (5th ed.) Moore and Persaud Chapter 16,17: p379-397, 399-405
  • Essentials of Human Embryology Larson Chapter 11 p207-228


  • Identify the components of a somite and the adult derivatives of each component.
  • Give examples of sites of (a) endochondral and (b) intramembranous ossification and to compare these two processes.
  • Identify the general times (a) of formation of primary and (b) of formation of secondary ossification centres, and (c) of fusion of such centres with each other.
  • Briefly summarise the development of the limbs.
  • Describe the developmental abnormalities responsible for the following malformations: selected growth plate disorders; congenital dislocation of the hip; scoliosis; arthrogryposis; and limb reduction deformities.

Development Overview

Below is a very brief overview using simple figures of 3 aspects of early musculoskeletal development. More detailed overviews are shown on other notes pages Mesoderm and Somite, Vertebral Column, Limb in combination with serial sections and Carnegie images.

Mesoderm Development

Mesoderm cartoon 01.jpg Cells migrate through the primitive streak to form mesodermal layer. Extraembryonic mesoderm lies adjacent to the trilaminar embryo totally enclosing the amnion, yolk sac and forming the connecting stalk.
Mesoderm cartoon 02.jpg Paraxial mesoderm accumulates under the neural plate with thinner mesoderm laterally. This forms 2 thickened streaks running the length of the embryonic disc along the rostrocaudal axis. In humans, during the 3rd week, this mesoderm begins to segment. The neural plate folds to form a neural groove and folds.
Mesoderm cartoon 03.jpg Segmentation of the paraxial mesoderm into somites continues caudally at 1 somite/90minutes and a cavity (intraembryonic coelom) forms in the lateral plate mesoderm separating somatic and splanchnic mesoderm.

Note intraembryonic coelomic cavity communicates with extraembryonic coelom through portals (holes) initially on lateral margin of embryonic disc.

Mesoderm cartoon 04.jpg Somites continue to form. The neural groove fuses dorsally to form a tube at the level of the 4th somite and "zips up cranially and caudally and the neural crest migrates into the mesoderm.

Limb Development

Somite cartoon5.png

Ossification Centres

Mouse limb showing primary ossification.[1]

Primary Ossification

Secondary Ossification

  • Secondary ossification centres develop in the cartilage epiphysis of the long bones.
  • No medulary cavity forms in a secondary ossification center.
  • Appears late in fetal development.
    • Used as a marker for term development if a secondary ossification centre present in either: head of femur, head of tibia, of head of humerus.
    • The last secondary centre to appear is the clavical medial epiphysis, that does not develop until 18 or 20 years.

Bone Structure


  • Diaphysis - shaft
  • Epiphysis - expanded ends
  • Metaphysis - connecting region (between diaphysis and epiphysial line)
  • Medullary Cavity - (marrow) cavity within the bone. Can also be identified as either red or yellow marrow.

Compact bone

  • (dense) no spaces or hollows in the bone matrix visible to the eye.
  • forms the thick-walled tube of the shaft (or diaphysis) of long bones, which surrounds the marrow cavity (or medullary cavity). A thin layer of compact bone also covers the epiphyses of long bones.

Trabecular bone

  • (cancellous or spongy bone) consists of delicate bars (spicules) and sheets of bone, trabeculae
  • branch and intersect to form a sponge-like network
  • ends of long bones (or epiphyses) consist mainly of trabecular bone.


Connective tissue covering the surface of bone (except articular surfaces).



Connective tissue lining inner surface of bone.

Bone Growth

  • Appositional growth occurs at either the periosteum (outer surface), or the endosteum (inner surface).
  • Osteoblasts secrete osteoid, a pre-bone material composed mainly of type I collagen that becomes mineralized.
  • Early bone matrix deposited in development and during repair is woven rather than lamellar in appearance and structure.
  • In development, there are 2 distinct types of bone formation (intramembranous and endochondral)

Bone Cells


  • derive from osteogenic stem cells the osteoprogenitor cells that differentiate to form pre-osteoblast then osteoblasts maturing to an osteocyte
  • osteoprogenitor cells - "resting cell" line the inner and outer surfaces of bone


  • mature bone-forming cells embedded in lacunae within the bone matrix
  • osteoblasts and osteocytes - secrete organic matrix of bone (osteoid), converted into osteocytes when become embedded in matrix (which calcifies soon after deposition)


Osteoclast.jpg Bone remodeling cycle.jpg

  • bone-resorbing multinucleated macrophage-like cells
  • origin- fusion of monocytes or macrophages, Blood macrophage precursor, Attach to bone matrix
  • seal a small segment of extracellular space (between plasma membrane and bone surface), HCl and lysosomes secreted into this space by osteoclasts dissolves calcium phosphate crystals (give bone rigidity and strength)
    • Resorptive bay - (Howship's lacuna) shallow bay lying directly under an osteoclast.
  • do not mistake for megakaryocytes, found in bone marrow not associated with bone matrix.
    • megakaryocytes are also multi-niucleated and form platelets

Bone Marrow

Hematopoietic and stromal cell differentiation
  • red marrow - mainly haematopoietic (myeloid) tissue, newborn has all red marrow
  • yellow marrow - mainly fat cells, found in diaphysis region of long bones
  • stromal cells - all other support cells not involved in haematopoiesis
Links: Blood Development

Marrow stroma components:

  1. osteoblasts - enclose the marrow compartment in bone tissue.
  2. endothelial and smooth muscle cells - organized into a complex vascular network composed of arterioles, capillaries, sinusoids, and a large central vein.
  3. nerves - sensory and sympathetic nerve fibres, glia, and perineural cells that innervate the marrow compartment to form a neural network.
  4. adipocytes - support metabolic functions of the bone marrow.
  5. stromal cells - support haematopoiesis and retain skeletal potential.

Bone Matrix

The bone matrix has 2 major components.

  • Organic portion composed of mainly collagen Type 1 (about 95%) and amorphous ground substance.
  • Inorganic portion (50% dry weight of the matrix) composed of hydroxyapatite crystals, calcium, phosphorus, bicarbonate, nitrate, Mg, K, Na.
    • storage calcium and phosphate
    • regulate blood calcium levels

Haversian Systems

Bone structure cartoon
  • also called osteons
  • Volkmann's canals - interconnect Haversian systems


  • concentric - surrounding each Haversian System
  • interstitial - bony plates that fill in between the haversian systems.
  • circumferential - layers of bone that underlie the periosteum and endosteum


  • osteocytes extending cytoplasmic processes into canaliculi
  • Additional Histology images: low | medium | high

Endochondral Ossification

Endochondral bone.jpg

See also Bone Histology

Endochondral ossification.jpg Endochondral ossification 2.jpg

Ossification endochondral 1c.jpg Articular cartilage.jpg

Links: Blue Histology - endochondral | Dev Biology - endochondral ossification | endochondral ossification animation

Intramembranous Ossification

See also Bone Histology

Ossification centre.jpg Intramembranous ossification centre.jpg

Links: Blue histology - intramembranous | intramembranous ossification animation

Human Fetal Head (12 week)

Fetal head medial.jpg Fetal head lateral.jpg


Fetal head section.jpg


The transcription factors Runx2 and Runx3 are essential for chondrocyte maturation, while Runx2 and Osterix are essential for osteoblast differentiation.


Osterix (OSX) encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus that has been shown to be essential for bone formation.


Osteogenesis Imperfecta

Osteogenesis Imperfecta (OI, brittle bone disease) originally described as a collagen 1 gene mutation, but can have several different genetic causes and can be classified into eight different types (I-VIII).[2]

  • COL1A1 and COL1A2 mutations
  • CRTAP and LEPRE1 mutations, in severe/lethal and recessively inherited osteogenesis imperfecta

Links: Musculoskeletal Abnormalities


  1. Antonella Galli, Dimitri Robay, Marco Osterwalder, Xiaozhong Bao, Jean-Denis Bénazet, Muhammad Tariq, Renato Paro, Susan Mackem, Rolf Zeller Distinct roles of Hand2 in initiating polarity and posterior Shh expression during the onset of mouse limb bud development. PLoS Genet.: 2010, 6(4);e1000901 PMID:20386744 | PMC2851570 | PLoS Genet.
  2. Jay R Shapiro, Paul D Sponsellor Osteogenesis imperfecta: questions and answers. Curr. Opin. Pediatr.: 2009, 21(6);709-16 PMID:19907330


Yingzi Yang Skeletal morphogenesis during embryonic development. Crit. Rev. Eukaryot. Gene Expr.: 2009, 19(3);197-218 PMID:19883365

E J Mackie, Y A Ahmed, L Tatarczuch, K-S Chen, M Mirams Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int. J. Biochem. Cell Biol.: 2008, 40(1);46-62 PMID:17659995


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Search April 2010

  • Musculoskeletal System Development - All (44637) Review (5065) Free Full Text (6601)
  • Musculoskeletal Development - All (44637) Review (5065) Free Full Text (6601)

Search Pubmed: Bone Development | developmental ossification | endochondral ossification | intramembranous ossification

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Cite this page: Hill, M.A. (2014) Embryology Musculoskeletal System - Bone Development. Retrieved July 25, 2014, from //

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Dr Mark Hill 2014, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G