Osteopetrosis

The osteopetrosis (also osteopetrosis, marble bone disease, Albers- Schonberg disease) is in the majority of cases caused by a hereditary sub-function of the bone resorbing cells ( osteoclasts). The undirected accumulation of bone tissue, the bone microarchitecture is disrupted and reduced mechanical stability. It therefore comes despite a substantial increase in bone mass to frequent bone fractures, which are often difficult to heal. As further complications can liver and spleen ( by extramedullary hematopoiesis ), decreased immune defense, seizures and injury of cranial nerves (especially blindness ) may occur.

Because the osteoclasts are formed in the context of hematopoiesis from precursor cells of the white blood cells, so far the only treatment is a bone marrow transplant, which leads to the formation of functional osteoclasts and reduce excessive sclerotherapy, involves a significant risk of hypercalcaemia.

Classification and inheritance

After their inheritance, the various forms of osteopetrosis are classified into two main groups:

• Autosomal recessive forms ( infantile malignant osteopetrosis, osteopetrosis with renal - tubular acidosis )
• Autosomal dominant forms ( type 1 ( ADOI ), type 2 ( ADOII, Albers- Schonberg disease) )

Course of autosomal recessive osteopetrosis

The autosomal recessive osteopetrosis usually begins in the first two years of life, the form with renal tubular acidosis slightly later than the infantile malignant form that can already lead to the birth of symptoms in the first few weeks. However, there are also milder recessive disease images that may overlap with the dominant osteopetrosis. If left untreated, the prognosis is usually poor. The only chance of recovery is currently in a bone marrow transplant, since the defective osteoclasts originate from hematopoietic lineage.

Course of autosomal dominant osteopetrosis

For the ADOI a generalized osteosclerosis with special emphasis on the cranial base is typical during the so-called "sandwich vertebrae " are characteristic of the ADOII that corresponds to the originally described by Albers- Schonberg disease on radiographs. Both forms are often dominant symptom during the growth spurt in adolescence, with the ADOI does not result in increased bone fractures, but also to an increased stability. Cosmetic problems can be caused by an enlargement of the lower jaw. The ADOI differs from all other forms, as it is caused by an overactive osteoblasts. The ADOII leads in contrast to frequent bone fractures and in some cases lead to complications similar to the malignant form (especially damage to the cranial nerves ). A causal therapy does not currently exist.

Genetic causes

• Autosomal recessive osteopetrosis:

Osteoclast - rich forms: TCIRG1, CLCN7, Ostm1, SNX10

Osteoclast - poor forms: TNFSF11 ( RANKL ), TNFRSF11A ( RANK )

• Autosomal recessive osteopetrosis with renal tubular acidosis: CAII
• Autosomal dominant osteopetrosis type 1: LRP5
• Autosomal dominant osteopetrosis type 2: CLCN7

Pathogenesis

Osteoblasts play a crucial role in the regulation of osteoclast activity. In defect in the CSF -1 synthesis, which is secreted by osteoblasts, osteoclasts can not be differentiated ( the fusion of mononuclear osteoclast progenitor cells is impossible). Since osteoclasts are not present, the bone is not decomposed, which leads to osteopetrosis.

And the c-fos transcription factor must be expressed in the osteoclast progenitor cells, thus further differentiation occurs. It has been switched off, the relevant gene in mice, leading to Osteoklastendefizienz and consequently to osteopetrosis.

Osteoclasts are in the area of ​​so-called detention area particularly rich in actin filaments and C -Src kinase. The gene silencing of the C- Src kinase leads to osteopetrosis in mice also because the adhesion is not present in the bone matrix.

Also give osteoclasts by exocytosis from lysosomal enzymes, including tartrate-resistant acid phosphatase (TRAP ) and cathepsin K, which promote bone loss. The genetically caused deficiency of cathepsin K leads to by skeletal abnormalities, short stature and increased bone mass pycnodysostosis marked, an important differential diagnosis of osteopetrosis.

In addition, osteoclasts possess in their brush border ( Ruffled Border ) the chloride channel ClC -7, the chloride in the lacuna between osteoclast and bone matrix releases. This is for the bone loss of central importance, since hydrochloric acid is formed in the lacuna. Mutations of ClC -7 lead to the autosomal recessive or autosomal dominant osteopetrosis.

Carbonic anhydrase II is a crucial enzyme in osteoclasts, which enables the formation of hydrogen ions and hydrogen of water and carbon dioxide. The hydrogen ions are pumped after the lacuna, the hydrogen is replaced by chloride in the smooth side of the cell ( bone matrix remote ) with participation from the anion exchanger 2 ( AE2). A genetic defect in the carbonic anhydrase II leads to osteopetrosis.