Skeletogenesis: Genetics

Abstract

The vertebrate skeleton is formed by two mechanisms – endochondral and intramembranous ossification. During intramembranous ossification, mesenchymal cells directly differentiate into osteoblasts. Endochondral ossification is a two‐step process during which bones are preformed as cartilage templates, which are subsequently replaced by bone. During this process, the inner cells of the cartilage condensation differentiate into chondrocytes, which proliferate and differentiate into hypertrophic chondrocytes producing a mineralised matrix. The outer cells differentiate into the perichondrium surrounding the cartilage template and later into osteoblasts, which produce a bone collar surrounding the hypertrophic region. Blood vessels from the bone collar invade the hypertrophic region in close association with bone‐resorbing osteoclasts and bone‐forming osteoblasts. The orchestrated formation, differentiation and degradation of cartilage and bone are regulated by a multitude of growth factors and transcriptional regulators, which will be discussed in this article.

Key Concepts:

  • During intramembranous ossification, mesenchymal progenitor cells differentiate directly into bone‐forming osteoblasts.

  • Endochondral ossification includes the formation of cartilage templates, which are subsequently replaced by bone and bone marrow.

  • Cells in the cartilage condensation represent bipotential osteochondroprogenitor cells that differentiate depending on their level of Sox9 into chondrocytes.

  • Ihh serves as a key regulator of endochondral ossification regulating chondrocyte proliferation, hypertrophic differentiation and ossification.

  • Ihh and Pthrp interact in a negative feedback mechanism to control the domain of columnar, high‐proliferating chondrocytes.

  • Pthrp negatively regulates cell cycle exit.

  • Runx2 and Mef2c activate chondrocyte differentiation.

  • Runx2 and Osterix are required to induce osteoblast differentiation.

  • The balance between Rankl and osteoprotegerin determines the differentiation of osteoclasts.

  • Chondrocyte differentiation is regulated by secreted growth factors, which activate distinct steps of the differentiation programme.

Keywords: endochondral ossification; cartilage; chondrocytes proliferation; chondrocyte differentiation; osteoblast; chondrocyte; osteoclast

Figure 1.

Schematic overview over endochondral ossification. (a) Mesenchymal cells condense to form the cartilaginous anlagen, which are surrounded by the perichondrium (yellow) (b). (c) In these anlagen, proliferating chondrocytes differentiate into round proliferating chondrocytes (red circles); columnar, high‐proliferating chondrocytes (orange); prehypertrophic chondrocytes (red); and hypertrophic chondrocytes (dark red), which mineralise their extracellular matrix and are subsequently degraded by osteoclasts and replaced by bone and bone marrow (blue). Adjacent to the hypertrophic zone, the perichondrium (yellow) mineralises to form the periosteum (light blue). (d) After birth, a secondary ossification centre is formed within the region of round chondrocytes near the joint. Remnants of the embryonic cartilage remain forming the growth plate, which ensures longitudinal growth of the bones until puberty.

Figure 2.

Distinct chondrocyte populations are characterised by the expression of different marker genes that regulate chondrocyte differentiation as outlined in the text. Colour code: round proliferating chondrocytes (red circles); columnar, proliferating chondroytes (orange); prehypertrophic chondrocytes (red); hypertrophic chondrocytes (dark red); perichondrium (yellow); periosteum (light blue); bone (blue).

Figure 3.

Signalling mechanisms orchestrating proliferation and differentiation of chondrocytes in the cartilage anlagen. Ihh is expressed in prehypertrophic chondrocytes and activates proliferation of columnar chondrocytes. In round chondrocytes, Ihh induces the expression of Pthrp, which, in turn, signals back to the columnar chondrocytes to inhibit hypertrophic differentiation and hence the differentiation of the Ihh‐expressing cell type. Ihh is negatively regulated by Fgf signalling and activated by Bmp signalling. In parallel, Bmp and Fgf regulate hypertrophy independent of Ihh.

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Further Reading

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Minina E , Wenzel HM , Kreschel C et al. (2001) BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 128(22): 4523–4534.

Naski MC , Wang Q , Xu J and Ornitz DM (1996) Graded activation of fibroblast growth factor receptor 3 by mutations causing achondroplasia and thanatophoric dysplasia. Nature Genetics 13: 233–237.

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Wuelling, Manuela, and Vortkamp, Andrea(Dec 2013) Skeletogenesis: Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005996.pub2]