title: Secretion of PDGF isoforms during osteoclastogenesis and its modulation by anti-osteoclast drugs.
abstract: In an attempt to identify secretory products of osteoclasts that mediate the coupling of bone formation to resorption, we found that along with osteoclast differentiation, PDGF-A gene expression increase occurred first, by 12 h after stimulation of bone marrow macrophages with M-CSF and RANKL, and peaked at 36 h. This was next followed by a progressive increase in PDGF-B gene expression until a peak at 60 h, when mature osteoclasts formed. Isoform-specific ELISA of the conditioned medium collected every 24 h revealed that all three of the isoforms of PDGF-AA, AB and BB were secreted, in this temporal order as differentiation proceeded. Their secretion was enhanced when osteoclasts were activated by placing them on dentin slices. The secretion of all three isoforms was decreased in cathepsin K-deficient osteoclasts compared with wild-type osteoclasts. Pharmacological inhibition of cathepsin K with odanacatib also inhibited the secretion of all three isoforms, as was also the case with alendronate treatment. The secretion of sphingosine-1-phosphate, which increased during osteoclastogenesis, was reduced from cathepsin K-deficient osteoclasts, and was inhibited by treatment with odanacatib more profoundly than with alendronate. Thus, all three isoforms of PDGF, which are secreted at distinct differentiation stages of osteoclasts, appear to have distinct roles in the cell-cell communication that takes place in the microenvironment of bone remodeling, especially from the osteoclast lineage to mesenchymal cells and vascular cells, thereby stimulating osteogenesis and angiogenesis.
authors.affiliation: Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan.
authors.forename: M Motiur
authors.initials: MM
authors.lastname: Rahman
authors.affiliation: Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Matsuoka
authors.affiliation: Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan. Electronic address: sunao@ncgg.go.jp.
authors.forename: Sunao
authors.initials: S
authors.lastname: Takeshita
authors.affiliation: Department of Bone and Joint Disease, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi 474-8511, Japan. Electronic address: kikeda@ncgg.go.jp.
authors.forename: Kyoji
authors.initials: K
authors.lastname: Ikeda
mesh_terms: D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D000077214:Becaplermin; D001713:Biphenyl Compounds / Q000494:pharmacology; D016723:Bone Remodeling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000172:deficiency; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D001713:Biphenyl Compounds; D015853:Cysteine Proteinase Inhibitors; D008246:Lysophospholipids; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C075278:platelet-derived growth factor A; C095477:platelet-derived growth factor AB; D000077214:Becaplermin; C060506:sphingosine 1-phosphate; D056657:Cathepsin K; C534132:Ctsk protein, mouse; C527128:odanacatib; D013110:Sphingosine; D019386:Alendronate
keywords: Bone remodeling; Cathepsin K; Odanacatib; Osteoclast; PDGF; S1P