title: Secretomes from mesenchymal stem cells participate in the regulation of osteoclastogenesis in vitro.
abstract: OBJECTIVE
  The receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors are novel clinically effective agents that inhibit osteoclast differentiation, function, and survival by binding to RANKL. Medication-related osteonecrosis of the jaw (MRONJ), caused as a result of treatment using denosumab, is a newly emerging type of bone necrosis, the exact pathogenesis of which is unknown. Several studies recently showed that the intravenous administration of mesenchymal stem cells (MSCs) improved the osteonecrosis of the jaw, and it was hypothesized that paracrine effects by secretomes from MSCs are the main constituent. Our aim was to investigate the effects of serum-free conditioned media from human MSCs (MSC-CM) and RANKL inhibitors on osteoclast differentiation.
  
  
  METHODS
  Cytokines included in MSC-CM were identified using the cytokine array analysis. MSC-CM was added to the culture medium of rat osteoclast precursors containing RANKL inhibitor. Osteoclast differentiation assays, immunohistochemistry, real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, and pit formation assays were performed.
  
  
  RESULTS
  MSC-CM included various cytokines such as the recruitment of cell osteogenesis angiogenesis and cell proliferation. MSC-CM promoted osteoclast differentiation and expression of master regulatory transcriptional factors for osteoclastogenesis. In addition, MSC-CM showed function maintenance in osteoclasts despite the presence of RANKL inhibitors.
  
  
  CONCLUSIONS
  Our findings suggest that secretomes in MSC-CM were related to the regulation of osteoclast differentiation, which may reduce the effect of RANKL inhibitors.
  
  
  CONCLUSIONS
  New combinations of drugs using factors included in MSC-CM have effective therapeutic modality for treating patients with MRONJ.
authors: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.|Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors: Kenichi
authors: K
authors: Ogata
authors: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan. w-kat@dent.niigata-u.ac.jp.
authors: Wataru
authors: W
authors: Katagiri
authors: Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors: Hideharu
authors: H
authors: Hibi
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D010010:Osteoclasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D053245:RANK Ligand / Q000037:antagonists & inhibitors*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D053245:RANK Ligand
keywords: Medication-related osteonecrosis; Osteoclasts; Osteogenesis; Paracrine effects; RANKL inhibitors; Secretome