Osteoblast-Osteoclast Communication and Bone Homeostasis

Abstract

Bone remodeling is tightly regulated by a cross-talk between bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoblasts and osteoclasts communicate with each other to regulate cellular behavior, survival and differentiation through direct cell-to-cell contact or through secretory proteins. A direct interaction between osteoblasts and osteoclasts allows bidirectional transduction of activation signals through EFNB2-EPHB4, FASL-FAS or SEMA3A-NRP1, regulating differentiation and survival of osteoblasts or osteoclasts. Alternatively, osteoblasts produce a range of different secretory molecules, including M-CSF, RANKL/OPG, WNT5A, and WNT16, that promote or suppress osteoclast differentiation and development. Osteoclasts also influence osteoblast formation and differentiation through secretion of soluble factors, including S1P, SEMA4D, CTHRC1 and C3. Here we review the current knowledge regarding membrane bound- and soluble factors governing cross-talk between osteoblasts and osteoclasts.

Keywords: bone; bone remodeling; osteoblast; osteoclast.

Figure 1

Strategies of osteoclastogenesis and osteoblastogenesis. (a) Osteoclastogenesis. Osteoclasts are tissue-specific macrophages derived from hematopoietic stem cells. In the presence of M-CSF, hematopoietic stem cells are committed to macrophage colony-forming units (CFU-M), the common precursor cells of macrophages and osteoclasts. When activated by the RANKL-RANK signal, CFU-M is further differentiated into mononucleated osteoclasts and subsequently fuse to become multinucleated osteoclasts. Multinucleated osteoclasts are fully matured upon a cognate interaction with osteoblasts and resorb bone matrix by secreting acids (H⁺), proteases (e.g., CTSK) and matrix metalloproteinases (MMPs) when they have a tight junction between the bone surface and basal membrane of osteoclasts to form a sealed compartment and then osteoclasts. (b) Osteoblastogenesis. Osteoblasts are derived from multipotent mesenchymal precursors and they are committed to osteoprogenitors and further differentiated into osteoblastic lineage through the expression of transcription factors RUNX2 and Osterix. They are continued to differentiation into matrix-producing mature osteoblasts and these cells have different fates: apoptosis, bone lining cells or osteocytes. A subpopulation of mature osteoblasts is surrounded by unmineralized osteoid and further differentiated into osteocytes, terminally differentiated bone cells in mineralized bone.

Figure 2

Key mediators of osteoblast-osteoclast interaction. Osteoblast-osteoclast communications are essential for fine-tuning of bone remodeling during bone homeostasis. (1) Osteoblasts and osteoclasts have direct contacts through the interactions between EFNB2-EPHB4, FAS-FASL and NRP1-SEMA3A to regulate cell proliferation, differentiation, and survival. (2) Osteoclast-mediated bone resorption releases TGF-β and IGF-1 from bone matrix to induce osteoblast-mediated bone formation. (3) Osteoblasts secrete M-CSF, RANKL, WNT5A that promote osteoclast formation and development and OPG and WNT16 that inhibit osteoclast activity. Conversely, osteoclasts secrete S1P, CTHRC1 and C3 that promote osteoblast differentiation and SEMA4D that suppresses osteoblasts differentiation.