A novel synthetic triazolotriazepine derivative JTT-606 inhibits bone resorption by down-regulation of action and production of bone resorptive factors.
In the search for a new class of bone-sparing agents, we have conducted random screening of the domestic chemical library using 45Ca release assay from prelabeled cultured neonatal mouse calvariae and identified a novel synthetic triazolotriazepine JTT-606 as a candidate for a potent inhibitor of bone resorption. JTT-606 inhibited 45Ca release dose dependently not only in the control calvarial culture but also in the stimulated cultures by interleukin-1alpha (IL-1alpha), fibroblast growth factor 2 (FGF-2), and parathyroid hormone (PTH). JTT-606 also inhibited both basal and stimulated osteoclast-like (OCL) cell formation in the coculture of mouse osteoblastic cells and bone marrow cells dose dependently, indicating its inhibitory effect on osteoclast differentiation. Ex vivo OCL cell formation by cultured bone marrow cells collected from ovariectomized (OVX) mice also was decreased dose dependently by in vivo application of JTT-606 to a level similar to that from sham-operated mice. Furthermore, JTT-606 inhibited resorbed pit formation by isolated mature osteoclasts as well as by unfractionated bone cells derived from rabbit long bones in the control and FGF-2-stimulated cultures dose dependently, indicating both the direct and the indirect actions of JTT-606 on mature osteoclast function. In addition, JTT-606 reduced production of IL-1alpha, tumor necrosis factor alpha (TNF-alpha), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in the human peripheral blood mononuclear cell culture. In vivo analyses of mature OVX rats revealed that the application of JTT-606 for 12 weeks increased the BMD of the lumbar spine and decreased the levels of serum osteocalcin and urine deoxypyridinoline to levels similar to those of 17beta-estradiol-treated OVX rats. We propose that JTT-606 may inhibit both osteoclast differentiation and function by down-regulating both the action and the production of bone resorptive factors. It is speculated that JTT-606 could be a potent agent for the treatment of osteopenic disorders with elevated osteoclastic bone resorption.
Chikazu
D
D
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Japan.
Shindo
M
M
Iwasaka
T
T
Katagiri
M
M
Manabe
N
N
Takato
T
T
Nakamura
K
K
Kawaguchi
H
H
D000818:Animals; D052176:Azulenes; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000503:physiopathology*; D002132:Calcium Radioisotopes / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D046508:Culture Techniques; D015536:Down-Regulation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism* / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D010010:Osteoclasts / Q000145:classification / Q000187:drug effects / Q000502:physiology; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000378:metabolism* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D012886:Skull; D013977:Tibia / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D052176:Azulenes; D002132:Calcium Radioisotopes; D007375:Interleukin-1; D015850:Interleukin-6; C411022:JTT 606; D010281:Parathyroid Hormone; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D016222:Fibroblast Growth Factor 2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor