Many Metabolic Genetic Disorders Involve Bone

A number of the more important examples of metabolic and genetic disorders that affect bone are listed in Table 48-10.

Osteogenesis imperfecta (brittle bones) is characterized by abnormal fragility of bones. The scleras are often abnormally thin and translucent and may appear blue owing to a deficiency of connective tissue. Four types of this condition (mild, extensive, severe, and variable) have been recognized, of which the extensive type occurring in the newborn is the most ominous. Affected infants may be born with multiple fractures and not survive. Over 90% of patients with osteogenesis imperfecta have mutations in the COL1A1 and COL1A2 genes, encoding proal(I) and proa2(I) chains, respectively. Over 100 mutations in these two genes have been documented and include partial gene deletions and duplications. Other mutations affect RNA splicing, and the most frequent type results in the replacement of glycine by another bulkier amino acid, affecting formation of the triple helix. In general, these mutations result in decreased expression of collagen or

Table 48-11. The principal proteins found in cartilage.

Proteins

Comments

Collagen proteins

Collagen type II

Collagens V, VI, IX, X, XI

90-98% of total articular cartilage collagen. Composed of three al(II) chains.

Type IX cross-links to type II collagen. Type XI may help control diameter of type II fibrils.

Noncollagen proteins

Proteoglycans Aggrecan Large non-aggregating proteoglycan DS-PG I (biglycan)1 DS-PG II (decorin) Chondronectin

Anchorin C II

The major proteoglycan of cartilage. Found in some types of cartilage.

Similar to CS-PG I of bone. Similar to CS-PG II of bone. May play role in binding type II collagen to surface of cartilage. May bind type II collagen to surface of chondrocyte.

1The core proteins of DS-PG I and DS-PG II are homologous to those of CS-PG I and CS-PG II found in bone (Table 48-9). A possible explanation is that osteoblasts lack the epimerase required to convert glucuronic acid to iduronic acid, the latter of which is found in dermatan sulfate.

1The core proteins of DS-PG I and DS-PG II are homologous to those of CS-PG I and CS-PG II found in bone (Table 48-9). A possible explanation is that osteoblasts lack the epimerase required to convert glucuronic acid to iduronic acid, the latter of which is found in dermatan sulfate.

in structurally abnormal proa chains that assemble into abnormal fibrils, weakening the overall structure of bone. When one abnormal chain is present, it may interact with two normal chains, but folding may be prevented, resulting in enzymatic degradation of all of the chains. This is called "procollagen suicide" and is an example of a dominant negative mutation, a result often seen when a protein consists of multiple different sub-units.

Osteopetrosis (marble bone disease), characterized by increased bone density, is due to inability to resorb bone. One form occurs along with renal tubular acido-sis and cerebral calcification. It is due to mutations in the gene (located on chromosome 8q22) encoding carbonic anhydrase II (CA II), one of four isozymes of carbonic anhydrase present in human tissues. The reaction catalyzed by carbonic anhydrase is shown below:

67 nm

67 nm

Reaction II is spontaneous. In osteoclasts involved in bone resorption, CA II apparently provides protons to neutralize the OH- ions left inside the cell when H+

ions are pumped across their ruffled borders (see above). Thus, if CA II is deficient in activity in osteoclasts, normal bone resorption does not occur, and osteopetrosis results. The mechanism of the cerebral calcification is not clear, whereas the renal tubular acidosis reflects deficient activity of CA II in the renal tubules.

Osteoporosis is a generalized progressive reduction in bone tissue mass per unit volume causing skeletal weakness. The ratio of mineral to organic elements is unchanged in the remaining normal bone. Fractures of various bones, such as the head of the femur, occur very easily and represent a huge burden to both the affected patients and to the health care budget of society. Among other factors, estrogens and interleukins-1 and -6 appear to be intimately involved in the causation of osteoporosis.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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