The Questions of Developmental Biology

The blood vessels also import the blood-forming cells that will reside in the marrow for
the duration of the organism's life. The number and activity of osteoclasts must be tightly
regulated. If there are too many active osteoclasts, too much bone will be dissolved, and
osteoporosis will result. Conversely, if not enough osteoblasts are produced, the bones are not
hollowed out for the marrow, and osteopetrosis results (Tondravi et al. 1997).
*Craniofacial cartilage development was discussed in Chapter 13 and will be revisited in Chapter 22; the development
of the limbs will be detailed in Chapter 16.
CCD may have been responsible for the phenotype of Thersites, the Greek soldier described in the Iliad as having
"both shoulders humped together, curving over his caved-in chest, and bobbing above them his skull warped to a point..
. ." (Dickman 1997).
Given the physiology of the osteoclast, we can now appreciate H. L. Mencken's (1919) prescient intuition: "Life is a
struggle, not against sin, not against the Money Power, not against malicious animal magnetism, but against hydrogen
ions."
Control of Cartilage Maturation at the Growth Plate
Recent discoveries of human and murine mutations resulting in abnormal skeletal
development have provided remarkable insights into how the differentiation, proliferation, and
patterning of chondrocytes are regulated.
Fibroblast Growth Factor Receptors
The proliferation of the epiphyseal growth plate cells and facial cartilage can be halted by
the presence of fibroblast growth factors (Deng et al. 1996; Webster and Donoghue 1996). These
factors appear to instruct the cartilage precursors to differentiate rather than to divide. In humans,
mutations of the receptors for fibroblast growth factors can cause these receptors to become
activated prematurely. Such mutations give rise to the major types of human dwarfism.
Achondroplasia is a dominant condition caused by mutations in the transmembrane region of
fibroblast growth factor receptor 3 (FGFR3). Roughly 95% of achondroplastic dwarfs have the
same mutation of FGFR3, a base pair substitution that converts glycine to arginine at position 380
in the transmembrane region of the protein. In addition, mutations in the extracellular portion of
the FGFR3 protein or in the tyrosine kinase intracellular domain may result in thanatophoric
dysplasia, a lethal form of dwarfism that resembles homozygous achondroplasia (see Figure 6.22;
Bellus et al. 1995; Tavormina et al. 1995).