Myeloid thrombomodulin lectin-like domain inhibits osteoclastogenesis and inflammatory bone loss.

Tsung-Lin Cheng,Jwu-Lai Yeh,Mei-Ling Ho,Shyh-Jou Shieh,Yin-Bo Jou,Chung-Hwan Chen,Guey-Yueh Shi,Ai-Lun Yang,Hua-Lin Wu,Chau-Zen Wang,Chao-Han Lai,Yan-Hsiung Wang

doi:10.1038/srep28340

Abstract

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/TMflox/flox) and from TM lectin-like domain deleted mice (TMLeD/LeD) compared with their respective controls. Micro-computerized tomography scans showed that ovariectomy-induced bone loss was more pronounced in TMLeD/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.

Highlights

(e.g., tartrate-resistant acid phosphatase (TRAP), cathepsin K (CATK), calcitonin receptor, and β3integrin) can be induced in the osteoclasts[2,3]
These results suggested that TM expression in monocytes/macrophages may be inversely related to osteoclastogenesis
We demonstrated that myeloid TM was reduced during osteoclastogenesis (Fig. 1), implicating a role of myeloid TM in high-turnover osteoporosis

Summary

Introduction

(e.g., tartrate-resistant acid phosphatase (TRAP), cathepsin K (CATK), calcitonin receptor, and β3integrin) can be induced in the osteoclasts[2,3] Other cells such as activated T-cells can modulate the formation of osteoclasts by secreting RANKL or osteoprotegerin, suggesting that the immune system might affect bone metabolism and homeostasis. TM belongs to the C-type lectin-like domain superfamily, and is expressed in various cell types such as keratinocytes, endothelial cells, myeloid-derived monocytes and macrophages[6,7,8]. Our previous study demonstrated that recombinant TMD1 (rTMD1) suppresses inflammation by directly binding to lipopolysaccharide (LPS)[19] Taken together, these studies reveal that TM functional domains can modulate inflammatory responses. The results would elucidate the significance of myeloid TM and its lectin-like domain in osteoporosis

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Conclusion