Myeloid thrombomodulin lectin-like domain inhibits osteoclastogenesis and inflammatory bone loss.
Osteoclastogenesis is an essential process during bone metabolism which can also be promoted by inflammatory signals. Thrombomodulin (TM), a transmembrane glycoprotein, exerts anti-inflammatory activities such as neutralization of proinflammatory high-mobility group box 1 (HMGB1) through TM lectin-like domain. This study aimed to identify the role of myeloid TM (i.e., endogenous TM expression on the myeloid lineage) in osteoclastogenesis and inflammatory bone loss. Using human peripheral blood mononuclear cells and mouse bone marrow-derived macrophages, we observed that the protein levels of TM were dramatically reduced as these cells differentiated into osteoclasts. In addition, osteoclastogenesis and extracellular HMGB1 accumulation were enhanced in primary cultured monocytes from myeloid-specific TM-deficient mice (LysMcre/TM(flox/flox)) and from TM lectin-like domain deleted mice (TM(LeD/LeD)) compared with their respective controls. Micro-computerized tomography scans showed that ovariectomy-induced bone loss was more pronounced in TM(LeD/LeD) mice compared with controls. Finally, the inhibiting effects of recombinant TM lectin-like domain (rTMD1) on bone resorption in vitro, and bone loss in both the ovariectomized model and collagen antibody-induced arthritis model has been detected. These findings suggested that the myeloid TM lectin-like domain may inhibit osteoclastogenesis by reducing HMGB1 signaling, and rTMD1 may hold therapeutic potential for inflammatory bone loss.
Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Tsung-Lin
TL
Cheng
Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan.|Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Chao-Han
CH
Lai
Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|International Research Center for Wound Repair and Regeneration (iWRR), National Cheng Kung University, Tainan, Taiwan.
Shyh-Jou
SJ
Shieh
Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Yin-Bo
YB
Jou
Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan.
Jwu-Lai
JL
Yeh
Graduate Institute of Exercise Science, University of Taipei, Taipei, Taiwan.
Ai-Lun
AL
Yang
Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Yan-Hsiung
YH
Wang
Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chau-Zen
CZ
Wang
Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Orthopedics, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Orthopedics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Orthopedics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
Chung-Hwan
CH
Chen
Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Guey-Yueh
GY
Shi
Department of Physiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.|Orthopaedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Taiwan.|Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Taiwan.
Mei-Ling
ML
Ho
Cardiovascular Research Center, National Cheng Kung University, Tainan, Taiwan.|Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hua-Lin
HL
Wu
D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000628:therapy*; D001862:Bone Resorption / Q000235:genetics / Q000628:therapy*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis; D000072417:Protein Domains; D000067996:RAW 264.7 Cells; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D018180:Thrombomodulin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D011994:Recombinant Proteins; D018180:Thrombomodulin