Intramembranous Bone and the Role of Neural Crest in Building the Head Skeleton
Bones form in two major ways. In one way, mesenchyme becomes cartilage and the cartilage is replaced by bone; this is called endochondral ossification, which we will describe in detail in Chapter 12. The other type of bone formation, where mesenchyme forms bones directly, is called intramembranous ossification (Figure 1). Both mesodermal and ectodermal (i.e., neural crest-derived) mesenchyme undergo intramembranous ossification in forming the face and skull.
Figure 1 Intramembranous ossification. (A) Mouse mesen- chyme cells condense and change shape to produce osteoblasts, which deposit osteoid matrix. Osteoblasts then become arrayed along the calcified region of the matrix. Osteoblasts that are embed- ded within the calcified matrix become osteocytes. (B) Bone formation in chick embryo heads (days 9–13) as revealed with alizarin red (which stains bone matrix). (A from Komori et al. 1997; B from Abzhanov et al. 2007, courtesy of A. Abzhanov.)
The pathway from neural crest to intramembranous bone begins when cranial neural crest cells, under the influence of BMPs from the head epidermis, proliferate and condense into compact nodules (Figure 2). High levels of BMPs induce these nodules to become cartilage, whereas lower lev- els of BMPs induce them to become pre-osteoblast progenitor cells that express the Runx2 transcription factor and the mRNA for collagens II and IX. Later, these cells downregulate Runx2 and begin expressing the osteopontin gene, giving them a phenotype similar to that of a developing chondrocyte (cartilage cell); thus, this stage is called a chondrocyte-like osteoblast. Under the influence of Indian hedgehog (which it secretes and probably receives in an autocrine fashion), the chondrocyte-like osteoblast becomes a mature osteoblast—a committed bone precursor cell (Abzhanov et al. 2007). The osteoblasts secrete a collagen-proteoglycan osteoid matrix that is able to bind calcium. osteoblasts that are embedded in the calcified matrix become osteocytes (bone cells). As calcification proceeds, bony spicules radiate out from the region where ossification began. Furthermore, the entire region of calcified spicules becomes surrounded by compact mesenchymal cells that form the periosteum (a membrane of cells that surrounds bone). The cells on the inner surface of the periosteum also become osteoblasts and deposit matrix parallel to the existing spicules. In this manner, many layers of bone are formed.
Figure 2 During craniofacial development, chick mesencephalic cranial neural crest cells migrate to become the mesenchyme of the future face and much of the skull. Cells of the early cranial skeletogenic condensations depend on BMP2/4/7 activities to form pre-osteoblastic progenitors (which eventually become bone), whereas high levels of BMP2 and/or BMP4 alone induce a chondrogenic (cartilage) fate. Differentiation into the chondrocyte-like osteoblasts is negatively regulated by both Indian hedgehog (IHH) and parathyroid hormone-related protein (PTHrP) activities that are probably autocrine. (After Abzhanov et al. 2007.)
Literature Cited
Abzhanov, A., D. R. Cordero, J. Sen, C. J. Tabin and J. A. Helms. 2007. Cross- regulatory interactions between Fgf8 and Shh in the avian frontonasal prominence. Congenital Anomalies 47: 136–148.
PubMed Link
Komori, T. and 14 others. 1997. Targeted disruption of Cba1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89: 755–764.
PubMed Link