Inhibition of osteoporosis by the αvβ3 integrin antagonist of rhodostomin variants.
Integrins are heterodimeric cell surface receptors that mediate cell-cell and cell-matrix interaction. The vitronectin and osteopontin receptor αvβ3 integrin has increased expression levels and is implicated in the adhesion, activation, and migration of osteoclasts on the bone surface as well as osteoclast polarization. αvβ3 integrin plays an important role in osteoclast differentiation and resorption. In addition, Arg-Gly-Asp (RGD)-containing peptides, small molecular inhibitors, and antibodies to αvβ3 integrin have been shown to inhibit bone resorption in vitro and in vivo. Here we examined the effects of a disintegrin HSA-ARLDDL a genetically modified mutant of rhodostomin conjugated with human serum albumin, which is highly selective of αvβ3, on RANKL-induced osteoclastogenesis and ovariectomy (OVX)-induced osteoporosis. In RANKL-induced osteoclastogenesis, HSA-ARLDDL significantly inhibited osteoclast formation, and IC50was at nM range. Post-treatment HSA-ARLDDL also inhibits osteoclast formation. Furthermore, weekly administration of HSA-ARLDDL significantly inhibits the increase in serum bone resorption marker levels and decrease in cancellous bone loss in tibia and femur induced by OVX. On the other hand, HSA-ARLDDL did not affect the differentiation and calcium deposition of osteoblasts. These results indicate that the highly selective and long-acting αvβ3 integrin antagonists could be developed as effective drugs for postmenopausal osteoporosis.
Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Section 1, Jen-Ai Rd., Taipei 10051, Taiwan; Material and Chemical Research Laboratories, Industrial Technology Research Institute, No.195, Section 4, Chung Hsing Rd., Hsinchu 31040, Taiwan.
Tzu-Hung
TH
Lin
Department of Orthopaedics, College of Medicine, National Taiwan University, No.1, Section 1, Jen-Ai Rd., Taipei 10051, Taiwan.
Rong-Sen
RS
Yang
Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Section 1, Jen-Ai Rd., Taipei 10051, Taiwan.
Huang-Ju
HJ
Tu
Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Section 1, Jen-Ai Rd., Taipei 10051, Taiwan.
Houng-Chi
HC
Liou
Department of Anatomy, Chang Gung University Medical College, No.259, Wenhua 1st Rd., Taoyuan City 33302, Taiwan.
Yen-Ming
YM
Lin
Department of Biochemistry, College of Medicine, Cheng-Kung University, No.1, University Road, Tainan City 701, Taiwan. Electronic address: wjcnmr@ncku.edu.tw.
Woie-Jer
WJ
Chuang
Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Section 1, Jen-Ai Rd., Taipei 10051, Taiwan. Electronic address: wenmei@ntu.edu.tw.
Wen-Mei
WM
Fu
D000818:Animals; D019483:Disintegrins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry; D010024:Osteoporosis / Q000188:drug therapy*; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D000072417:Protein Domains; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism
D019483:Disintegrins; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D010455:Peptides; D012709:Serum Albumin; C072026:rhodostomin; C047981:arginyl-glycyl-aspartic acid
Bone mineral density; Bone resorption; Integrin; Osteoclast; Ovariectomy