IntroductionThe amount of bone remodeling is controlled by the balance between bone formation and bone resorption (1-3). Many osteopenic diseases, including osteoporosis, rheumatoid arthritis, Paget disease, and lytic bone metastases of malignancies are characterized by progressive and excessive bone resorption by osteoclasts, which are multinucleated giant cells that originate from hematopoietic cells (2). A TNF family member, receptor activator of NF-κB ligand (RANKL), which is expressed as a membrane-bound protein in osteoblasts and stromal cells, promotes the differentiation of osteoclast precursor cells into osteoclasts (4, 5). Gene-targeted mice deficient in RANKL expression show severe osteopetrosis with complete absence of osteoclast formation (5). These findings indicate that RANKL is an essential factor responsible for osteoclast differentiation.

Tartrate-resistant acid phosphatase (TRAP) is highly expressed in bone-resorbing osteoclasts and activated macrophages. It has been suggested that a redox-active iron in the binuclear iron center of TRAP could have the capacity to react with hydrogen peroxide to produce highly destructive reactive oxygen species (ROS). Here we show that TRAP can generate ROS in vitro and that cells over-expressing TRAP produce higher amounts of intracellular ROS than their parent cells. We further demonstrate that these ROS can be targeted to destroy collagen and other proteins. In resorbing osteoclasts, TRAP was found in transcytotic vesicles transporting matrix degradation products through the cell, suggesting that TRAP-facilitated fragmentation of endocytosed material takes place in a specific cellular compartment. These results suggest that bone matrix degradation occurs not only extracellularly in the resorption lacunae but also intracellularly in the transcytotic vesicles. We propose that proteins containing redox-active iron could represent a novel mechanism of physiological fragmentation of organic molecules. This mechanism could be important in tissue remodeling and as a defense mechanism of phagocytosing cells.

IntroductionThe amount of bone remodeling is controlled by the balance between bone formation and bone resorption (1-3). Many osteopenic diseases, including osteoporosis, rheumatoid arthritis, Paget disease, and lytic bone metastases of malignancies are characterized by progressive and excessive bone resorption by osteoclasts, which are multinucleated giant cells that originate from hematopoietic cells (2). A TNF family member, receptor activator of NF-κB ligand (RANKL), which is expressed as a membrane-bound protein in osteoblasts and stromal cells, promotes the differentiation of osteoclast precursor cells into osteoclasts (4, 5). Gene-targeted mice deficient in RANKL expression show severe osteopetrosis with complete absence of osteoclast formation (5). These findings indicate that RANKL is an essential factor responsible for osteoclast differentiation.

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