Severe Osteoporosis in Mice Lacking Osteoclastogenesis Inhibitory Factor/Osteoprotegerin

Mizuno, Atsuko; Amizuka, Norio; Irie, Kazuharu; Murakami, Akihiko; Fujise, Nobuaki; Kanno, Takeshi; Satô, Yasushi; Nakagawa, N.; Yasuda, Hisataka; Mochizuki, Shin-ichi; Gomibuchi, Takashi; Yano, Kouji; Shima, Nobuyuki; Washida, Naohiro; Tsuda, Eisuke; Morinaga, Tsutomu; Higashio, Kanji; Ozawa, Hiroki

doi:10.1006/bbrc.1998.8697

Cited by 724 publications

(483 citation statements)

References 23 publications

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“…However, the involvement of RANKL and OPG in PDL tissue during orthodontic tooth movement has not yet been examined. In that regard, OPG-deficient mice provide a useful animal model for osteoporosis without other abnormalities (Bucay et al, 1998;Mizuno et al, 1998). From this study of OPG-deficient mice, we report immunocytochemical evidence suggesting that OPG is an important negative regulator of osteoclast induction in periodontal tissues during experimental movement of incisors.…”

mentioning

confidence: 81%

“…Eight-week-old OCIF/JcL OPG (-/-) mice and their wild-type OPG (ϩ/ϩ) littermates (Saitama Experimental Animals Supply Co. Ltd., Saitama, Japan) (Mizuno et al, 1998) were used in the experiment. An elastic band (a stretched piece of rubber) was set between the right and left incisors in the maxilla of OPG-deficient and wild-type mice for 2 or 5 days.…”

Section: Materials and Methods Animal Use Protocol And Experimentsmentioning

confidence: 99%

“…Therefore, OPG inhibits ovariectomy-induced bone loss in rats (Bateman et al, 2000). In contrast, OPG deficiency results in severe osteoporosis in both humans and experimental animals (Bucay et al, 1998;Mizuno et al, 1998;Yano et al, 1999).…”

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confidence: 99%

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Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

et al. 2002

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Osteoprotegerin (OPG) is a novel secreted member of the tumor necrosis factor (TNF) receptor superfamily that negatively regulates osteoclastogenesis. The receptor activator of the NFKB ligand (RANKL) is one of the key regulatory molecules in osteoclast formation and binds to OPG. In this study, it was suggested that OPG and RANKL are involved in alveolar bone remodeling during orthodontic tooth movement. We examined RANKL localization and osteoclast induction in periodontal tissues during experimental movement of incisors in OPG-deficient mice. To produce orthodontic force, an elastic band was inserted between the upper right and left incisors for 2 or 5 days, and the dissected maxillae were examined for cytochemical and immunocytochemical localization of tartrate-resistant acid phosphatase (TRAP), vacuolar-type H ϩ -ATPase, and RANKL. Compared to wild-type OPG (ϩ/ϩ) littermates, TRAP-positive multinucleated cells were markedly induced in the periodontal ligament (PDL) on the compressed side and in the adjacent alveolar bone of OPG-deficient mice. These multinucleated cells exhibited intense vacuolar-type H ϩ -ATPase along the ruffled border membranes. Because of accelerated osteoclastic resorption in OPG-deficient mice, alveolar bone was severely destroyed and partially perforated at 2 and 5 days after force application. In both wild-type and OPG-deficient mice, RANKL expression became stronger at 2 and 5 days after force application than before force application. There was no apparent difference in intensity of RANKL expression between OPG (ϩ/ϩ) littermates and OPGdeficient mice. In both wild-type and OPG-deficient mice, expression of RANKL protein was detected in osteoblasts, fibroblasts, and osteoclasts mostly located in resorption lacunae. These results suggest that during orthodontic tooth movement, RANKL and OPG in the periodontal tissues are important determinants regulating balanced alveolar bone resorption. Anat Rec 266:218 -225, 2002.

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confidence: 81%

Section: Materials and Methods Animal Use Protocol And Experimentsmentioning

confidence: 99%

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Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

et al. 2002

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“…The interaction between RANKL and RANK is critical in the formation and activation of osteoclasts, and inhibition by OPG results in inhibition of bone resorption. The critical role of these TNF family members is highlighted by in vivo studies where mice deficient in RANK or RANKL have extensive osteopetrosis due to a lack of functional osteoclasts (17,18), whereas OPG knock out mice have severe osteoporosis (19).…”

Section: The Rank/rankl/opg Systemmentioning

confidence: 99%

The pathogenesis of the bone disease of multiple myeloma

Edwards

Zhuang

Mundy

2008

Bone

152

120

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Multiple myeloma is a fatal hematologic malignancy associated with clonal expansion of malignant plasma cells within the bone marrow and the development of a destructive osteolytic bone disease. The principal cellular mechanisms involved in the development of myeloma bone disease are an increase in osteoclastic bone resorption, and a reduction in bone formation. Myeloma cells are found in close association with sites of active bone resorption, and the interactions between myeloma cells, and other cells within the specialized bone marrow microenvironment are essential, both for tumor growth and the development of myeloma bone disease. This review discusses the many different factors which have been implicated in myeloma bone disease, including the evidence for their role in myeloma and subsequent therapeutic implications.

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“…(16,17) In vivo analyses using OPG-deficient mice, which develop severe early-onset osteoporosis with increased osteoclast numbers, supported the preceding theory about the physiologic function of OPG CRDs. (18,19) However, the physiologic function of DDHDs and the HBD of OPG was still unclear.…”

Section: Introductionmentioning

confidence: 99%

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

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The amount of the receptor activator of NF-kB ligand (RANKL) on the osteoblastic cell surface is considered to determine the magnitude of the signal input to osteoclast precursors and the degree of osteoclastogenesis. Previously, we have shown that RANKL is localized predominantly in lysosomal organelles, but little is found on the osteoblastic cell surface, and consequently, the regulated subcellular trafficking of RANKL in osteoblastic cells is important for controlled osteoclastogenesis. Here we have examined the involvement of osteoprotegerin (OPG), which is currently recognized as a decoy receptor for RANKL, in the regulation of RANKL behavior. It was suggested that OPG already makes a complex with RANKL in the Golgi apparatus and that the complex formation is necessary for RANKL sorting to the secretory lysosomes. It was also shown that each structural domain of OPG is indispensable for exerting OPG function as a traffic regulator. In particular, the latter domains of OPG, whose physiologic functions have been unclear, were indicated to sort RANKL molecules to lysosomes from the Golgi apparatus. In addition, the overexpression of RANK-OPG chimeric protein, which retained OPG function as a decoy receptor but lost the function as a traffic regulator, inhibited endogenous OPG function as a traffic regulator selectively in osteoblastic cells and resulted in the upregulation of osteoclastogenic ability despite the increased number of decoy receptor molecules. Conclusively, OPG function as a traffic regulator for RANKL is crucial for regulating osteoclastogenesis at least as well as that as a decoy receptor. ß

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Severe Osteoporosis in Mice Lacking Osteoclastogenesis Inhibitory Factor/Osteoprotegerin

Cited by 724 publications

References 23 publications

Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

Osteoclast induction in periodontal tissue during experimental movement of incisors in osteoprotegerin‐deficient mice

The pathogenesis of the bone disease of multiple myeloma

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

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