BoneKEy-Osteovision | Perspective
The pathogenesis of osteoclast diseases: Some knowns, but still many unknowns
Miep H Helfrich
Julie C Crockett
Lynne J Hocking
Fraser P Coxon
DOI:10.1138/20060249
Abstract
Genetic diseases of osteoclasts include those in which osteoclast function is compromised, such as in osteopetrosis, and diseases of osteoclast overactivity, such as the pagetic disorders. The genetic basis of these conditions is now largely known and this review gives an update on the most recent findings and functional studies supporting the role of genes in disease pathogenesis. Loss-of-function mutations in the genes TCIRG1, CLCN7, OSTM1 and PLEKHM1 are found in autosomal recessive osteopetrosis, and current evidence suggests they are mechanistically linked by their involvement in the trafficking of acidic vesicles in osteoclasts. The genetic defects in osteoclast-poor osteopetrosis remain to be found. Autosomal dominant osteopetrosis type II is also caused by loss-of-function mutations in CLCN7. Juvenile Paget's disease is caused by loss-of-function mutations in the gene for osteoprotegerin (OPG), TNFRSF11B, and is an endocrine disorder which can be treated by reconstituting OPG levels. The other pagetic diseases appear to be more osteoclast-autonomous. Classic Paget's disease of bone (PDB) is associated with mutations in SQSTM1, the complex syndrome known as inclusion body myositis with PDB and frontotemporal dementia (IBMPFD) with mutations in VCP, and the severe pagetic disorders early-onset PDB, familial expansile osteolysis and expansile skeletal hyperphosphatasia are all associated with mutations in TNFRSF11A, the gene for RANK. The common pathway affected by these genes is less easily deduced, but most likely involves perturbation of the proteasomal degradation pathway. We suggest that these pagetic disorders have many similarities with “inclusion body diseases” of the brain and skeletal muscle. Further understanding of pagetic disorders may require animal models that faithfully represent the pathology seen in patients, since cellular models show only part of the complex disease pathology.
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