Dok-3 and Dok-1/-2 Adaptors Play Distinctive Roles in Cell Fusion and Proliferation During Osteoclastogenesis and Cooperatively Protect Mice From Osteopenia

Biochem Biophys Res Commun. 2018 Apr 15;498(4):967-974. doi: 10.1016/j.bbrc.2018.03.090. Epub 2018 Mar 17.

Abstract

Bone mass is determined by coordinated acts of osteoblasts and osteoclasts, which control bone formation and resorption, respectively. Osteoclasts are multinucleated, macrophage/monocyte lineage cells from bone marrow. The Dok-family adaptors Dok-1, Dok-2 and Dok-3 are expressed in the macrophage/monocyte lineage and negatively regulate many signaling pathways, implying roles in osteoclastogenesis. Indeed, mice lacking Dok-1 and Dok-2, the closest homologues with redundant functions, develop osteopenia with increased osteoclast counts compared to the wild-type controls. Here, we demonstrate that Dok-3 knockout (KO) mice also develop osteopenia. However, Dok-3 KO, but not Dok-1/-2 double-KO (DKO), mice develop larger osteoclasts within the normal cell-count range, suggesting a distinctive role for Dok-3. Indeed, Dok-3 KO, but not Dok-1/-2 DKO, bone marrow-derived cells (BMDCs) generated larger osteoclasts with more nuclei due to augmented cell-to-cell fusion in vitro. In addition, while Dok-1/-2 DKO BMDCs generated more osteoclasts, Dok-1/-2/-3 triple-KO (TKO) BMDCs generated osteoclasts increased in both number and size. Furthermore, Dok-1/-2/-3 TKO mice showed the combined effects of Dok-3 and Dok-1/-2 deficiency: severe osteopenia with more and larger osteoclasts. Together, our findings demonstrate that Dok-3 and Dok-1/-2 play distinctive but cooperative roles in osteoclastogenesis and protect mice from osteopenia, providing physiological and pathophysiological insight into bone homeostasis.

Keywords: Cell-to-cell fusion; Dok; Osteoclastogenesis; Osteopenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Bone Diseases, Metabolic / prevention & control*
  • Bone Marrow Cells / cytology
  • Cell Count
  • Cell Culture Techniques
  • Cell Fusion
  • Cell Proliferation
  • Cell Size
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Mice
  • Mice, Knockout
  • Osteoclasts / cytology*
  • Osteogenesis*
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / physiology*

Substances

  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • Dok1 protein, mouse
  • Dok2 protein, mouse
  • Dok3 protein, mouse
  • Phosphoproteins
  • RNA-Binding Proteins