title: Osteoclast precursor interaction with bone matrix induces osteoclast formation directly by an interleukin-1-mediated autocrine mechanism.
abstract: Interleukin-1 (IL-1) and tumor necrosis factor (TNF) mediate bone resorption in a variety of diseases affecting bone. Like TNF, IL-1 is secreted by osteoclast precursors (OCPs), but unlike TNF, it does not induce osteoclast formation directly from OCPs in vitro. TNF induces IL-1 expression and activates c-Fos, a transcription factor required in OCPs for osteoclast formation. Here, we examined whether IL-1 can induce osteoclast formation directly from OCPs overexpressing c-Fos and whether interaction with bone matrix affects OCP cytokine expression. We infected OCPs with c-Fos or green fluorescent protein retrovirus, cultured them with macrophage colony-stimulating factor and IL-1 on bone slices or plastic dishes, and assessed osteoclast and resorption pit formation and expression of IL-1 by OCPs. We used a Transwell assay to determine whether OCPs secrete IL-1 when they interact with bone matrix. IL-1 induced osteoclast formation directly from c-Fos-expressing OCPs on plastic. c-Fos-expressing OCPs formed osteoclasts spontaneously on bone slices without addition of cytokines. OCPs on bone secreted IL-1, which induced osteoclast formation from c-Fos-expressing OCPs in the lower Transwell dishes. The bone matrix proteins dentin sialoprotein and osteopontin, but not transforming growth factor-beta, stimulated OCP expression of IL-1 and induced c-Fos-expressing OCP differentiation into osteoclasts. Osteoclasts eroding inflamed joints have higher c-Fos expression compared with osteoclasts inside bone. We conclude that OCPs expressing c-Fos may induce their differentiation directly into osteoclasts by an autocrine mechanism in which they produce IL-1 through interaction with bone matrix. TNF could induce c-Fos expression in OCPs at sites of inflammation in bone to promote this autocrine mechanism and thus amplify bone loss.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Yao
authors.forename: Lianping
authors.initials: L
authors.lastname: Xing
authors.forename: Chunlin
authors.initials: C
authors.lastname: Qin
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schwarz
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects*; D001862:Bone Resorption / Q000378:metabolism* / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000378:metabolism; D010750:Phosphoproteins; D011498:Protein Precursors / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D012795:Sialoglycoproteins; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology; D048069:Tumor Necrosis Factors / Q000378:metabolism / Q000494:pharmacology*; D000099311:Dentin Sialophosphoprotein
chemical_list: D016326:Extracellular Matrix Proteins; D007375:Interleukin-1; D053495:Osteopontin; D010750:Phosphoproteins; D011498:Protein Precursors; D016760:Proto-Oncogene Proteins c-fos; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D048069:Tumor Necrosis Factors; D000099311:Dentin Sialophosphoprotein; C506896:Spp1 protein, mouse; C506897:Spp1 protein, rat