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Even though disorders of the skeleton are alone rare, they are of clinical significance since of their overall frequency. Several efforts have been made in the past to identify disease groups in order to facilitate diagnosis as well as to draw conclusions regarding likely underlying path mechanisms. Usually, skeletal disorders have been subdivided into dysostoses, defined as malformations of individual bones or groups of bones, plus osteochondrodysplasias, defined as developmental disorders of chondro-osseous tissue. In light of the recent advances in molecular genetics, however, several phenotypically parallel skeletal diseases comprising the conventional categories turned out not to be based on defects in frequent genes or physiological pathways. In this article, the study present a classification based on a combination of molecular pathology plus embryology, taking into account the significance of development for the understanding of bone diseases.
Disorders of Skeletal Patterning
The skeleton arises as of three distinct sites. The axial skeleton, consisting of the vertebrae as well as ribs, originates as of the somites; the appendicle skeleton has its origin in mesenchymal cells located in the lateral plate mesoderm. Most of the craniofacial bones are of neural-crest origin. Disorders affecting the craniofacial skeleton have been discussed in detail elsewhere (Wilkie and Morriss- Kay 2001) moreover will therefore not be presented here.
The Axial Skeleton
The axial skeleton, consisting of the vertebrae plus the dorsal part of the ribs, is entirely derived as of the somites, transient organizational structures of the developing embryo located on both sides of the neural tube.
Somites are blocks of epithelial cells by means of a periodic structure that originate as of the paraxial mesoderm. The formation of new somites in addition to their detachment as of the paraxial mesoderm has to occur in a highly ordered fashion simultaneously on both sides of the neural tube, in a craniocaudal direction. Timed regulation of the formation in addition to budding of new somites is given by oscillations of cycling genes that lead to waves of notch signalling sweeping up the paraxial mesoderm as of the posterior to the anterior pole (Saga and Takeda 2001). In addition to this molecular clock, a stable gradient of Fgf8 expression as of the posterior to the anterior pole of the embryo allows a spatial coordination of somite border formation. Dll proteins are notch ligands that reside at the cell surface. Their degree of difference expression determines the size as well as the polarity of the somites. Any disturbance in this division outcomes in abnormally spaced somites as well as in fusion of adjacent somites, as exemplified in the mouse mutant pudgy, which carries a mutation in Dll3 (Kusumi et al. 1998).
As the somite moves rostrally, it matures plus differentiates into the dermatomyotome-a formation giving rise to the entire appendicular moreover axial musculature, as well as to the dorsal epithelium in addition to the sclerotome, the primary origin of the axial skeleton. The signalling molecule sonic hedgehog (Shh) is the chief signal as of the notochord/floor plate that initiates and controls sclerotome formation. It is obvious that any disturbance of this course will outcome in abnormal anlagen of the backbone and therefore in vertebral malformations.
Conditions by means of Vertebral Malformations
Abnormalities of the ribs plus/or vertebrae are a relatively common finding in human malformation syndromes. Those that primarily involve the axial skeleton are summarized under the term "spondylocostal dysostoses" (SCDs). Even though the causes of the majority of these genetically heterogeneous conditions stay undiscovered, one type of dominant SCD has been shown to be caused by mutations in DLL3 (Bulman et al. 2000).
Similar to the pudgy mutant in the mouse, which is caused by mutations in the mouse ortholog, Dll3 (Kusumi et al. 1998), affected persons show a wide variety of vertebral malformations, including fusions as well as half vertebrae. Vertebral malformations are frequently observed in Robinow syndrome, a condition that will be discussed further below. Robinow syndrome is caused by mutations in ROR2, an orphan receptor tyrosine kinase (Afzal et al. 2000; van Bokhoven et al. 2000). The role of ROR2 in somite development remains to be determined.
The Appendicular Skeleton
The limb skeleton originates as of the lateral plate mesoderm, which forms the limb bud as the outcome of a series of interactions by means of the overlying ectoderm. The mesenchymal cells of the growing limb bud begin to differentiate to form the various tissues of the limb in a proximodistal sequence, by means of structures being laid down progressively as of a region of undifferentiated cells at the tip of the limb bud, known as the "progress zone."
The positional identity moreover therefore differentiation of each cell is controlled by a three-dimensional coordinate system consisting of the dorsoventral, proximodistal, in addition to anteroposterior axes. Each axis is controlled by a particular set of signalling molecules/pathways produced by a defined population of cells. Three signalling regions have been identified: the apical ectodermic ridge (AER), mediating limb bud outgrowth (proximodistal axis); ectoderm covering the sides of the bud, governing the dorsoventral pattern; and the zone of polarizing activity (ZPA), controlling the anteroposterior pattern.
Several of the signalling molecules that are produced by these signalling centres have been identified plus characterized. Receptors have been identified, as well as intracellular signalling transduction pathways are being unravelled (Capdevila and Izpisua Belmonte 2001).
The AER is an anatomical structure consisting of densely packed ectoderm cells located at the very tip of the limb bud. Several different fibroblast growth factors (FGFs) are expressed moreover secreted by the AER and have been shown to be essential in addition to sufficient to initiate plus control outgrowth of the limb. FGF signalling is conveyed through the FGF receptors, which are expressed in the underlying mesenchyme. As discussed below, the FGF-signalling system is in addition significant in later stages of development, when FGFs control skeletal morphogenesis as well as growth.
The ZPA is a region of mesenchyme located at the posterior limb bud margin. Shh is expressed in this region moreover has been shown to be the main mediator of anteroposterior patterning (Chiang et al. 1996).
Oestrogen loss is the main cause of osteoporosis, a major health problem in industrialized countries. Accelerated bone loss during the postmenopausal phase is characterized by reduced osteoblast function and increased resorption by osteoclasts, whereas the slow decay typical of osteoporosis at higher ages is mainly due to impaired osteoblast activity. Mutations in oestrogen receptor b moreover in the enzyme aromatise, which converts androgens to oestrogen, lead to osteoporotic phenotypes (Smith et al. 1994; Bilezikian et al. 1998). Affected individuals are usually of tall stature, since of a delay of bone maturation plus growth plate closure, which illustrates the significance of sex hormones for skeletal development.
Cross Talk flanked by Osteoblast and Osteoclast
The model of a balanced competition flanked by osteoblasts as well as osteoclasts in homeostasis predicts that a weakening of one cell type outcomes in either bone accumulation or bone loss. This is demonstrated by a simple experiment: A specific ablation of mature osteoblasts by transgenic expression of herpes virus thymidine kinase under control of the osteocalcin promoter causes a ganciclovir- inducible in addition to reversible bone loss, since bone resorption apparently proceeds normally (Corral et al. 1998). Even though osteoblasts moreover osteoclasts are antagonists, they communicate by means of each other intensively.
This is exemplified by the osteoporotic (op) mouse mutant, which lacks macrophage-colony stimulating factor (M-CSF), a soluble growth factor that is produced by bone stromal cells and promotes proliferation of early osteoclast precursors (Felix et al. 1990).