Osteoclasts are bone-resorbing cells that play a pivotal role in bone remodeling. Osteoclasts form large multinuclear giant cells by fusion of mononuclear osteoclasts. How cell fusion is mediated, however, is unclear. We identify the dendritic cell–specific transmembrane protein (DC-STAMP), a putative seven-transmembrane protein, by a DNA subtraction screen between multinuclear osteoclasts and mononuclear macrophages. DC-STAMP is highly expressed in osteoclasts but not in macrophages. DC-STAMP–deficient mice were generated, and osteoclast cell fusion was completely abrogated in homozygotes despite normal expression of osteoclast markers and cytoskeletal structure. As osteoclast multinucleation was restored by retroviral introduction of DC-STAMP, loss of cell fusion was directly attributable to a lack of DC-STAMP. Defects in osteoclast multinucleation reduce bone-resorbing activity, leading to osteopetrosis. Similar to osteoclasts, foreign body giant cell formation by macrophage cell fusion was also completely abrogated in DC-STAMP–deficient mice. We have thus identified an essential regulator of osteoclast and macrophage cell fusion, DC-STAMP, and an essential role of osteoclast multinucleation in bone homeostasis.

Chondrocyte hypertrophy during endochondral ossification is a well-controlled process in which proliferating chondrocytes stop proliferating and differentiate into hypertrophic chondrocytes, which then undergo apoptosis. Chondrocyte hypertrophy induces angiogenesis and mineralization. This step is crucial for the longitudinal growth and development of long bones, but what triggers the process is unknown. Reactive oxygen species (ROS) have been implicated in cellular damage; however, the physiological role of ROS in chondrogenesis is not well characterized. We demonstrate that increasing ROS levels induce chondrocyte hypertrophy. Elevated ROS levels are detected in hypertrophic chondrocytes. In vivo and in vitro treatment with N-acetyl cysteine, which enhances endogenous antioxidant levels and protects cells from oxidative stress, inhibits chondrocyte hypertrophy. In ataxia telangiectasia mutated (Atm)–deficient (Atm−/−) mice, ROS levels were elevated in chondrocytes of growth plates, accompanied by a proliferation defect and stimulation of chondrocyte hypertrophy. Decreased proliferation and excessive hypertrophy in Atm−/− mice were also rescued by antioxidant treatment. These findings indicate that ROS levels regulate inhibition of proliferation and modulate initiation of the hypertrophic changes in chondrocytes.

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Radical hysterectomy and bilateral pelvic lymphadenectomy were done on 875 patients diagnosed with cervical carcinoma Stages IB (484 patients), IIA (96 patients), and IIB (295 patients). The number of positive nodes was 0 in 620 patients (N0), one in 98 patients (N1), two to three in 80 patients (N2), four to 18 in 45 patients (N4), and unresectable in 32 patients. Cumulative 5-year survival rates were 89%, 81%, 63%, 41%, and 23%, respectively. Significant survival reduction rates (P less than 0.05) from N0 to N1 were insignificant in Stage IB patients (92% versus 91%), in those patients without parametrial invasion (92% versus 90%), and in those with parametrial invasion (76% versus 72%). Survival reduction rates (P less than 0.01) from N1 to N2 resulted from a reduction in IB patients without parametrial invasion (100%-71%, P less than 0.01). Survival reduction rates (P less than 0.05) from N2 to N4 resulted from a reduction in Stage IIB patients with parametrial invasion (60%-29%, P less than 0.05). These figures suggest that the number of positive nodes is a more indicative prognostic factor than the existence of nodal metastasis, and that the 5-year survival rates of those patients with one positive node can be improved up to the level of those without nodal metastasis.