Musculoskeletal System - Bone Development

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Introduction

Endochondral bone
Bone femur diagram
Bone femur

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. For details on specific bone differentiation in human development see Bone Development Timeline.


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 | Muscle Timeline | Tendon | Diaphragm | Lecture - Musculoskeletal Development | Abnormalities | Limb Abnormalities | Cartilage Histology | Bone Histology | Skeletal Muscle Histology | Category:Musculoskeletal
Historic Embryology  
1902 - Pubo-femoral Region | Spinal Column and Back | Body Segmentation | Cranium | Body Wall, Ribs, and Sternum | Limbs | 1901 - Limbs | 1902 - Arm Development | 1906 Human Embryo Ossification | 1907 - Muscular System | Skeleton and Limbs | 1910 - Skeleton and Connective Tissues | Muscular System | Coelom and Diaphragm | 1921 - External body form | Connective tissues and skeletal | Muscular | Diaphragm | 1943 Human Embryonic, Fetal and Circumnatal Skeleton

Some Recent Findings

Historic images of the skull by Vesalius
  • Disruption of Scube2 impairs endochondral bone formation[1] "SCUBE2 (signal peptide-CUB-EGF domain-containing protein 2) belongs to a secreted and membrane-tethered multi-domain SCUBE protein family composed of 3 members found in vertebrates and mammals. Recent reports suggested that zebrafish scube2 could facilitate sonic hedgehog (Shh) signaling for proper development of slow muscle. However, whether SCUBE2 can regulate the signaling activity of two other hedgehog ligands (Ihh and Dhh), and the developmental relevance of the SCUBE2-induced hedgehog signaling in mammals remain poorly understood. In this study, we first showed that as compared with SCUBE1 or 3, SCUBE2 is the most potent modulator of IHH signaling in vitro. In addition, gain and loss-of-function studies demonstrated that SCUBE2 exerted an osteogenic function by enhancing Ihh-stimulated osteoblast differentiation in the mouse mesenchymal progenitor cells." Sonic hedgehog
  • Vascularization of primary and secondary ossification centres in the human growth plate[2] "The switch from cartilage template to bone during endochondral ossification of the growth plate requires a dynamic and close interaction between cartilage and the developing vasculature. Vascular invasion of the primarily avascular hypertrophic chondrocyte zone brings chondroclasts, osteoblast- and endothelial precursor cells into future centres of ossification. ...Vascularization of ossification centres of the growth plate was mediated by sprouting of capillaries coming from the bone collar or by intussusception rather than by de-novo vessel formation involving endothelial progenitor cells. Vascular invasion of the joint anlage was temporally delayed compared to the surrounding joint tissue."
More recent papers
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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.
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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 | Journal Searches


Search term: Bone Embryology

Nilüfer Çakır-Özkan, Sinan Eğri, Esengül Bekar, B Zuhal Altunkaynak, Yonca Betil Kabak, Elfide Gizem Kıvrak The Use of Sequential VEGF- and BMP2-Releasing Biodegradable Scaffolds in Rabbit Mandibular Defects. J. Oral Maxillofac. Surg.: 2016; PubMed 27663536

Serap Uslu, Arzu Gercek Irban, Arel Gereli, Elif Ilgaz Aydinlar, Pinar Elpen, Umit Ince The effect of femoral nerve block on fracture healing via expressions of growth factors and β-catenin. Folia Histochem. Cytobiol.: 2016; PubMed 27654016

Kentaro Suzuki, Daisuke Matsumaru, Shoko Matsushita, Aki Murashima, Michael Ludwig, Heiko Reutter, Gen Yamada Epispadias and the associated embryopathies; genetic and developmental basis. Clin. Genet.: 2016; PubMed 27649475

Selly Sayuri Suzuki, Aguinaldo Silva Garcez, Hideo Suzuki, Edilson Ervolino, Won Moon, Martha Simões Ribeiro Low-level laser therapy stimulates bone metabolism and inhibits root resorption during tooth movement in a rodent model. J Biophotonics: 2016; PubMed 27647761

Dandan Chen, Wenyu Fu, Wenxin Zhuang, Cui Lv, Fengjie Li, Xin Wang Therapeutic effects of intranigral transplantation of mesenchymal stem cells in rat models of Parkinson's disease. J. Neurosci. Res.: 2016; PubMed 27617772

Adult Human Skeleton

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

Textbooks

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

Objectives

  • 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 Mesoderm cartoon 02.jpg Mesoderm cartoon 03.jpg Mesoderm cartoon 04.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. 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. 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. 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.[3]

Primary Ossification

  • Primary ossification centres are the first sites of bone formation and where cartilage has begun to degenerate. In long bones, this lis generally located mid-diaphysis (shaft). In other bones (e.g. base of skull) these are the initial locations of bone formation.

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.

Endochondral Ossification

Most of the bony skeleton forms by this process, that replaces a developmental cartilage template with bone.

Longitudinal views of endochondral bone formation in mouse limbs.[4]
100%
a - Prx1+ progenitors from lateral plate mesoderm proliferate to populate the emerging limb bud. b - Cells nearest the centre undergo mesenchymal condensation, express Col2a1 as they enter a chondrogenic differentiation program, and deposit a cartilage template. c to d - Differentiating cells upregulate Col10a1 as they become hypertrophic, which triggers local formation of a bone collar and vascularization of the cartilage template. Invading blood vessels deliver an influx of haematopoietic cells that give rise to osteoclasts which excavate the cartilage template, and Osx1+ osteoblast progenitors and other blood cell types that populate the newly formed marrow cavity. d - A longitudinal growth axis is established when vascularization and osteoclast-mediated resorption bisect the presumptive skeletal element, producing two growth plates with opposing directionality. A perpendicular growth axis is driven by periosteal osteoblasts and allows the bone to grow in width. e - Within the remodelled cartilage template, bone-forming osteoblasts are derived from Osx1+ cells arriving with the invading vasculature, as well as hypertrophic Col10a1+ chondroctyes that transdifferentiate as they exit the growth plate into the marrow cavity. As bones grow in length and width, a second wave of vascularization forms the secondary ossification centres. f - Mature endochondral bone.


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

Only specific parts of the skeleton form by this process, where bone forms by direct ossification of mesenchyme without a pre-existing cartilage template. This process occurs in regions of the skull and the clavicle. See also this recent review.[5]

See also Bone Histology

Ossification centre.jpg Intramembranous ossification centre.jpg



Links:

Human Fetal Head (12 week)

Fetal head medial.jpg Fetal head lateral.jpg

Meckel.jpg

Fetal head section.jpg

Bone Structure

Terminology

  • 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.
Bone-femur.jpg

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.

Periosteum

Connective tissue covering the surface of bone (except articular surfaces). The embryonic origin of this layer is still controversial.

Periosteum.jpg

Endosteum

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

Osteoblasts

  • 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

Osteocytes

  • 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)

Osteoclasts

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

Lamellae

  • 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

Cells

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


Molecular

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

Osterix

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.

Abnormalities

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).[6]

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


Links: Musculoskeletal Abnormalities

References

  1. Yuh-Charn Lin, Steve R Roffler, Yu-Ting Yan, Ruey-Bing Yang Disruption of Scube2 impairs endochondral bone formation. J. Bone Miner. Res.: 2015; PubMed 25639508
  2. Sonja M Walzer, Erdal Cetin, Ruth Grübl-Barabas, Irene Sulzbacher, Beate Rueger, Werner Girsch, Stefan Toegel, Reinhard Windhager, Michael B Fischer Vascularization of primary and secondary ossification centres in the human growth plate. BMC Dev. Biol.: 2014, 14;36 PubMed 25164565 | BMC Dev Biol.
  3. 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 PubMed 20386744 | PMC2851570 | PLoS Genet.
  4. Valerie S Salazar, Laura W Gamer, Vicki Rosen BMP signalling in skeletal development, disease and repair. Nat Rev Endocrinol: 2016; PubMed 26893264
  5. Christopher J Percival, Joan T Richtsmeier Angiogenesis and intramembranous osteogenesis. Dev. Dyn.: 2013, 242(8);909-22 PubMed 23737393
  6. Jay R Shapiro, Paul D Sponsellor Osteogenesis imperfecta: questions and answers. Curr. Opin. Pediatr.: 2009, 21(6);709-16 PubMed 19907330


Reviews

Masaharu Takigawa CCN2: a master regulator of the genesis of bone and cartilage. J Cell Commun Signal: 2013, 7(3);191-201 PubMed 23794334

| MC3709051 | J Cell Commun Signal. Jerry R Dwek The periosteum: what is it, where is it, and what mimics it in its absence? Skeletal Radiol.: 2010, 39(4);319-23 PubMed 20049593

Yingzi Yang Skeletal morphogenesis during embryonic development. Crit. Rev. Eukaryot. Gene Expr.: 2009, 19(3);197-218 PubMed 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 PubMed 17659995


Articles

Journals

  • BONE is an interdisciplinary forum for the rapid publication of original articles and reviews on basic, translational, and clinical aspects of bone and mineral metabolism.

Search PubMed

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

Additional Images

Terms

Bone Terms  
Bone Development
  • canaliculus - (plural, canaliculi) small channel in the bone matrix in which an osteocyte process lies and communicates with other osteocytes and the Haversian canal.
  • diaphysis - anatomical term that refers to the shaft of long bones.
  • endosteum - inner layer of cells lining the medullary cavity of long bones and is highly vascularised. A similar cellular region and fibrous layer lies on the outside of the bone, the periosteum.
  • epiphysis - anatomical term that refers to the expanded ends of long bones.
  • haematopoiesis (Greek, haima = "blood"; poiesis = "to make") the process of blood cell formation. In the adult, this occurs only in the bone marrow. In the embryo this occurs in other locations (yolk sac, liver, spleen, thymus) until bone develops.
  • Haversian canal - the central canal of an osteon (Haversian system) in compact bone, within which blood vessels and nerves travel throughout the bone.
  • Haversian system - (osteon) the historic name for the functional unit of compact bone. Consists of a central canal (Haversian canal) surrounded by lamellar bone matrix within which osteocytes reside. Named after Clopton Havers (1650-1702) an English physician and anatomist. PMID 12999959
  • Howship's lacuna - (resorptive bay) the historic name for the shallow bay or cavity lying directly under an osteoclast. This is the site of bone matrix resorption. Named after John Howship (1781–1841) a British anatomist who identified this region in 1820.
  • lacuna - (Latin, lacuna = “ditch, gap” diminutive form of lacus = “lake”) lacunae is the plural, cavity in bone or cartilage for cell.
  • lamellar bone - the highly organized strong bone matrix deposited in concentric sheets with a low proportion of osteocytes. Many collagen fibers parallel to each other in the same layer.
  • medullary cavity - (bone marrow) refers to the cavity within the bone, that is lined with cells (endosteum) and filled with bone marrow. in the adult, this can also be identified as either red or yellow marrow.
  • metaphysis - anatomical term that connecting region, that lies between the diaphysis and epiphysial line.
  • osteon - (Haversian system) the functional unit of compact bone. Consists of a central canal (Haversian canal) surrounded by lamellar bone matrix within which osteocytes reside.
  • periosteum - the cellular region and fibrous layer lying on the outside of the bone.
  • resorptive bay - (Howship's lacuna) the shallow bay or cavity lying directly under an osteoclast. This is the site of bone matrix resorption.
  • suture - in the skull a form of articulation where the contiguous margins of the bones are united by a thin layer of fibrous tissue.
  • woven bone - the first deposited weaker bone matrix with many osteocytes and a matrix disorganized structure. Replaced by lamellar bone. Seen in developing, healing and bone disease.
Other Terms Lists  
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Cite this page: Hill, M.A. (2016) Embryology Musculoskeletal System - Bone Development. Retrieved September 25, 2016, from https://embryology.med.unsw.edu.au/embryology/index.php/Musculoskeletal_System_-_Bone_Development

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© Dr Mark Hill 2016, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G