Transmigration of mature multinucleated osteoclasts
Osteoclasts (OCs) are large multinucleated cells of hematopoietic origin formed by the differentiation and fusion of mononuclear monocyte–macrophage lineage precursors after stimulation by RANKL and macrophage colony-stimulating factor (M-CSF). OC access to the bone surface requires precursor recruitment from the circulation into bone and a capacity to migrate to find their way to suitable stromal sites for their development into bone-resorptive mature multinucleated OCs (MMOCs). Mononucleated osteoclasts precursors (pre-OCs) have the capacity to transmigrate through endothelial cells. MMOCs also exhibit several features usually involved in cell invasion such as expression of the proto-oncogene c-src. Disruption of c-src leads to osteopetrosis in mice, resulting in the excessive accumulation of bone matrix caused by defective OC functions. Matrix metalloproteinases (MMPs), which play a major role in tumor cell invasion and metastasis, are also involved in OC function by promoting their recruitment and the degradation of the mineralized bone matrix. Finally, OCs exhibit podosomes, highly dynamic actin-rich structures involved in adhesion, migration, and matrix degradation, and sealing zones insuring attachment to bone surface.
A new gene involved in osteopetrosis
Osteopetrosis is a genetically and clinically heterogeneous bone disorder characterized by a reduction in bone resorption and a generalized net accumulation of skeletal mass. The causative genes identified so far all play a role in acidification of the resorption lacuna, and loss-of-function mutations in these genes severely affect mature osteoclast function. The CA2 (carbonic anhydrase 2) gene produces the protons necessary for acidification of the resorption lacuna, the extracellular compartment between the bone tissue and the osteoclast where bone resorption occurs. The α3 subunit of the H+ ATPase is involved in the transportation of these protons through the ruffled border into the resorption lacuna, while chloride channel 7 (ClC-7) translocates chloride ions to maintain electroneutrality.
Pathological role of osteoclast costimulation in arthritis-induced bone loss
Osteoclasts, multinucleated cells of hematopoietic origin that degrade the bone matrix, are regulated by immunoregulatory molecules under both physiological and pathological conditions. Combined deficiency of Fc receptor common γsubunit (FcRγ) and DNAX-activation protein 12 (DAP12) results in a complete lack of osteoclasts. In addition to RANK, the receptor for RANK ligand (RANKL), the Ig-like receptors associated with FcRγ and DAP12 have been recognized as essential receptors for osteoclastogenesis. This observation established that Ig-like receptors function as osteoclast costimulatory receptors, which are crucial for bone homeostasis under physiological conditions.
Regulation of cancer cell migration and bone metastasis by RANKL
Bone metastases are a frequent complication of many cancers that result in severe disease burden and pain. It is now acknowledged that the microenvironment of the local host tissue actively participates in the propensity of certain cancers to metastasize to specific organs, and that bone provides an especially fertile ’soil’. In the case of breast cancers, the local chemokine milieu is now emerging as an explanation for why these tumors preferentially metastasize to certain organs. However, as the inhibition of chemokine receptors in vivo only partially blocks metastatic behavior, other factors must exist that regulate the preferential metastasis of breast cancer cells.
GM-CSF stimulates osteoclastogenesis: therapeutic caution is required
Patients with a variety of tumors, including those with breast cancer, are often treated with granulocyte-monocyte colony stimulating factor (GM-CSF), a cytokine that increases white cell counts. GM-CSF stimulates the proliferation and differentiation of hematopoietic precursors, thereby replenishing blood cells ravaged by chemotherapy.
 Download here the slide set presented by Prof. Friedlander, on Thursday, March 29th. |
