Osteopetrosis

• Molecules affecting osteoclast differentiation and function.
• The binding of receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) produced by osteoblasts to RANK on osteoclast precursors induces osteoclast differentiation;
• in animals with defects in these genes, no osteoclasts are observed.
• In disorders of acidification—there are no primary defects in differentiation reduced osteoclastic bone resorption that results in a high bone mass.
• including defects in carbonic anhydrase II (CAII), the osteoclast-specific proton pump (encoded by TCIRG1, also termed ATP6i), and the gene encoding a chloride channel (CLCN7)

• Normal bone resorption by Osteoclasts:
1. Differentiation from granulocyte-macrophage precursors → osteoclast
2. Osteoclast attachment to bone
3. Creation of a ruffled border (resorptive surface)
4. Acidification of bone to dissolve and digest the mineral matrix
• Generation of protons by carbonic anhydrase II (CAII)
• Transport of protons through the ruffled border by a vacuolar proton pump
• Maintenance of electroneutrality in the ruffled border by chloride exchange

• Defects in Osteopetrosis:
• Loss-of-function mutations impairing the acidification process through trafficking and/or fusion of lysosome-related organelles to the ruffled border
• eg of mutations:
• Osteoclast vacuolar proton pump (TCIRG1, MIM 604592)
• H+-Cl− exchange transporter 7 (CLCN7, MIM 602727)
• Account for nearly 70% of autosomal-recessive osteopetrosis
• CAII enzyme (MIM 611492)
• Stabilizing β-subunit of the H+-Cl− exchange transporter 7 (OSTM1, MIM 607649)
• Lysosome-associated protein involved in vesicular trafficking (PLEKHM1, MIM 611466)

• Osteoclast-Poor Forms of Autosomal Recessive Osteopetrosis:
• Mutations in tumor necrosis factor ligand superfamily member 11 (TNFSF11, MIM 602642)
• Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A, MIM 603499)
• Interference with receptor activator of nuclear factor κ-B receptor and ligand signaling pathway
• Impact on osteoblast activation of osteoclastogenesis

• Due to poor bone reabsorption and net bone formation → Rather than conferring strength, the overly dense bone architecture forms a structural brittle bone that predisposes to fracture → give rise to skeletal deformity and dental abnormalities
• Can interfere with
• Mineral homeostasis expansion of bone into marrow cavities
• Manifest as profound anaemia, bleeding, frequent infections, and hepatosplenomegaly from extramedullary hematopoiesis.
• Cranial nerve foramina
• The latter can lead to blindness, deafness, and nerve palsies
 

flowchart LR
    A[Poor bone resorption and<br>net bone formation]
    B[Overly dense<br>bone architecture]
    C[Structural brittle bone]
    D[Skeletal deformity<br>and dental abnormalities]
    E[Interference with<br>mineral homeostasis]
    F[Expansion of bone<br>into marrow cavities]
    G[Profound anaemia, bleeding,<br>frequent infections,<br>hepatosplenomegaly from<br>extramedullary<br>hematopoiesis]
    H[Interference with cranial<br>nerve foramina]
    I[Blindness, deafness,<br>and nerve palsies]

    A --> B
    B --> C
    C --> D
    D --> E
    E --> F
    F --> G
    E --> H
    H --> I

• Skeletal survey is sufficient to make the diagnosis.
• Because of the wide gamut of pathognomonic radiographic features of osteopetrosis,
• Parallel bands of dense bone can give the appearance of “bone-within-bone” or “endobones.”
• Seen most often in the
• pelvis,
• long bones,
• Club-shaped flaring of the metaphyses of long bones with cortical thinning (Erlenmeyer flask bone deformity) and transverse metaphyseal lucent bands reflect a failure of metaphyseal remodeling but are not exclusive to osteopetrosis
• phalanges,
• Vertebrae
• Vertebrae can also be uniformly dense or take on a “sandwich vertebrae” or “rugger-jersey” appearance (when a normal-appearing vertebral midbody is sandwiched between dense bands along the superior and inferior endplates).
• Evidence of new or healing fractures may be found, and skull changes can include calvarial and basilar thickening as well as poor sinus development.