Growth/differentiation factor-15 inhibits differentiation into osteoclasts--a novel factor involved in control of osteoclast differentiation.
Survival and capability of cancer cells to form metastases fundamentally depend on interactions with their microenvironment. Secondary tumors originating from prostate carcinomas affect remodeling of bone tissue and can induce both osteolytic and osteocondensing lesions. However, particular molecular mechanisms responsible for selective homing and activity of cancer cells in bone microenvironment have not been clarified yet. Growth/differentiation factor-15 (GDF-15), a distant member of the TGF-beta protein family, has recently been associated with many human cancers, including prostate. We show that both pure GDF-15 and the GDF-15-containing growth medium of 1,25(OH)(2)-vitamin D(3)-treated prostate adenocarcinoma LNCaP cells suppress formation of mature osteoclasts differentiated from RAW264.7 macrophages and bone-marrow precursors by M-CSF/RANKL in a dose-dependent manner. GDF-15 inhibits expression of c-Fos and activity of NFkappaB by delayed degradation of IkappaB. Moreover, GDF-15 inhibits expression of carbonic anhydrase II and cathepsin K, key osteoclast enzymes, and induces changes in SMAD and p38 signaling. The lack of functional osteoclasts can contribute to accumulation of bone matrix by reduction of bone resorption. These results unveil new role of GDF-15 in modulation of osteoclast differentiation and possibly in therapy of bone metastases.
Vanhara
Petr
P
Department of Experimental Biology, Faculty of Science, Masaryk University, Kotlárská 2, CZ 611 37 Brno, Czech Republic.
Lincová
Eva
E
Kozubík
Alois
A
Jurdic
Pierre
P
Soucek
Karel
K
Smarda
Jan
J
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005269:Femur / Q000166:cytology; D055436:Growth Differentiation Factor 15 / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors; D053245:RANK Ligand / Q000494:pharmacology; D000071681:Tartrate-Resistant Acid Phosphatase; D013997:Time Factors
D017077:Culture Media, Conditioned; D055436:Growth Differentiation Factor 15; D007527:Isoenzymes; D016328:NF-kappa B; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D016173:Macrophage Colony-Stimulating Factor; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D056657:Cathepsin K; D024402:Carbonic Anhydrase II; D002117:Calcitriol