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Genetic regulation of osteoclast development and function

Key Points

  • Bone mass is controlled by the relative activities of osteoblasts, which are bone forming cells, and osteoclasts, which degrade the tissue.

  • The osteoclast is a cell of haematopoietic origin and a member of the monocyte/macrophage lineage. Development of osteoclasts requires the concerted actions of a range of cytokines, steroids and lipids, which act directly on precursors themselves and indirectly by targeting a combination of mesenchymal supportive cells and those in the lymphoid lineage.

  • The capacity of mature osteoclasts to resorb bone is cytokine driven and depends on their ability to recognize the matrix, polarize, and secrete protons and a collagenolytic enzyme.

  • So far, most genetic mutations that regulate bone mass, whether natural or generated by targeted deletions, are associated with the osteoclast.

  • Mutations can be inherent to the osteoclast and precursor, or found in proteins that are produced by lymphoid or mesenchymal tissue, which regulate the survival, differentiation and/or function of the mature bone-resorbing cell.

  • Use of the data obtained in genetic studies has led to the development of several drugs that selectively suppress osteoclast function, thereby helping to maintain bone mass.

Abstract

Osteoclasts are the principal, if not exclusive, bone-resorbing cells, and their activity has a profound impact on skeletal health. So, disorders of skeletal insufficiency, such as osteoporosis, typically represent enhanced osteoclastic bone resorption relative to bone formation. Prevention of pathological bone loss therefore depends on an appreciation of the mechanisms by which osteoclasts differentiate from their precursors and degrade the skeleton. The past five years have witnessed important insights into osteoclast formation and function. Many of these discoveries have been made through genetic experiments that involved the rare hereditary disorder osteopetrosis.

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Figure 1: Regulation of osteoclast formation and function.
Figure 2: Regulation of the resorptive activity of osteoclasts.
Figure 3: Mutations that lead to osteoclast gain of function.
Figure 4: Role of T cells and IL-7 in oestrogen-mediated bone loss in vivo.
Figure 5: RANK ligand might induce osteoblast and osteoclast differentiation.

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Acknowledgements

We thank M. Whyte for assistance with the gain of function section. The authors are recipients of National Institutes of Health support.

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Authors and Affiliations

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DATABASES

LocusLink

Bcl2

Ctsk

Fos

Fosl1

Ifnar1

INPP5D

SPI1

SQSTM1

Tcirg1

Tnf

Tnfrsf11a

TNFRSF11A

Tnfrsf11b

TNFRSF11B

Tnfsf11

Traf6

OMIM

Glanzmann thrombasthenia

hereditary expansile polyostotic osteolytic dysplasia

osteopetrosis

osteoporosis

Paget disease of bone

PDB1

PDB4

pycnodysostosis

Glossary

OSTEOCLASTOGENESIS

The generation of osteoclasts from their monocytic precursors.

POLARIZATION

The capacity of the osteoclast to generate asymmetric protein distributions and shapes, which allow it to attach to and resorb bone.

VACUOLAR PROTON PUMPS

Ruffled-membrane-residing electrogenic H+ATPases that transport protons into the resorptive microenvironment.

BONE-MARROW SPACE

The cavity within bone that contains the bone marrow.

CORTEX

The densest portion of bone, which comprises approximately 80% of the skeletal mass and is an important structural component.

OSTEOLYTIC

The degradation of bone in pathological conditions.

HAEMATOPOIETIC

Giving rise to the cellular elements of the blood, such as white blood cells, red blood cells and platelets.

POLYKARYON

A multinucleated cell.

METACHROMATIC CEMENT LINE

A histological marker that delineates the depth of a remodelling site.

ANKYRIN REPEATS

A repeating amino-acid motif that mediates protein–protein interactions.

DENDRITIC CELLS

Phagocytic antigen-presenting cells that trigger adaptive immunity to a wide range of pathogens.

FOCAL ADHESIONS

Sites at which cells make contact with their substratum, which contain clusters of integrins with their extracellular parts bound to extracellular matrix proteins and their intracellular parts attached to actin filaments.

PLATELETS

Fragments of megakaryocytes that circulate in all mammals and regulate blood coagulation.

PROTEASOME

A large intracellular complex that degrades proteins to which ubiquitin has been added by a process that requires ATP.

RENAL TUBULAR ACIDOSIS

Low blood pH owing to the failure of renal tubules to regulate plasma bicarbonate concentration.

CEREBRAL CALCIFICATION

The deposition of calcium salts in the brain, which is typically identified by imaging techniques.

SCLEROSING

The process of pathologically enhancing bone mass, which is typically detected by radiography or densitometry.

ZYMOGEN

An inactive form of an enzyme, which requires proteolytic processing for activation.

FOUNDER EFFECT

A gene mutation that is observed in high frequency in a specific population owing to its presence in a single ancestor or a small number of ancestors.

OOPHORECTOMY

The surgical removal of the ovaries, which results in systemic oestrogen deficiency.

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Teitelbaum, S., Ross, F. Genetic regulation of osteoclast development and function. Nat Rev Genet 4, 638–649 (2003). https://doi.org/10.1038/nrg1122

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