Eph-Ephrin Signaling Mediates Cross-Talk Within the Bone Microenvironment

Abstract

Skeletal integrity is maintained through the tightly regulated bone remodeling process that occurs continuously throughout postnatal life to replace old bone and to repair skeletal damage. This is maintained primarily through complex interactions between bone resorbing osteoclasts and bone forming osteoblasts. Other elements within the bone microenvironment, including stromal, osteogenic, hematopoietic, endothelial and neural cells, also contribute to maintaining skeletal integrity. Disruption of the dynamic interactions between these diverse cellular systems can lead to poor bone health and an increased susceptibility to skeletal diseases including osteopenia, osteoporosis, osteoarthritis, osteomalacia, and major fractures. Recent reports have implicated a direct role for the Eph tyrosine kinase receptors and their ephrin ligands during bone development, homeostasis and skeletal repair. These membrane-bound molecules mediate contact-dependent signaling through both the Eph receptors, termed forward signaling, and through the ephrin ligands, referred to as reverse signaling. This review will focus on Eph/ ephrin cross-talk as mediators of hematopoietic and stromal cell communication, and how these interactions contribute to blood/ bone marrow function and skeletal integrity during normal steady state or pathological conditions.

Keywords: Eph-ephrin communication; bone marrow mesenchymal stem cells; bone marrow microenvironment; hematopoietic stem cells; musculoskeletal pathology; osteogenic differentiation; osteoimmunology; vasculature.

Figure 1

The bone microenvironment. A schematic representation of the resident cells within the bone microenvironment during homeostasis. These cellular components include fibroblasts (fb), stroma, bone marrow stem cells (BMSC), osteoprogenitors (OP), obsteoblasts (OB), bone lining cells (BLC), osteocytes (Oty), the periosteum (P), nerves, Schwann cells (sc), nerve bundle (nb), arterioles (A), endothelial cells (E), Pericytes (Pr), CXCL12-abundant reticular cells (CAR), also known as Leptin Receptor+ mesenchymal stromal cells, adipocytes (Ad), hematopoietic stem cells (HSC), hematopoietic progenitor (HPC) cells, lymphoid progenitors (LP), monocytes (m), macrophage (mc) and osteoclasts (OC). These cells form specific niches to regulate haematopoiesis and osteogenesis and thus maintain skeletal integrity.

Figure 2

Bone Remodeling. A schematic overview of the cells and main molecular processes involved during the stages of bone remodeling starting with the activation stage, where hematopoietic stem cells (HSC) give rise to pre-osteoclasts of the myeloid lineage that are recruited to the injury site. This is followed by the resorption stage where the pre-osteoclasts undergo maturation and fusion to form mature multinucleated osteoclasts that resorb the bone matrix. The reversal stage sequesters bone marrow stromal stem cells (BMSC) and osteoblast progenitors to the repair site, which is followed by the formation stage, where the bone matrix is synthesized and osteoid is laid down. The mineralization stage involves the mineralization of the osteoid and regeneration of new bone. These cellular responses are mediated by molecular interactions and signaling cascades. The major contributors include the C-FMS, M-CSF, the RANK/RANL/OPG axis, CXCL12/CXCR4 signaling and Eph-ephrin communication.

Figure 3

Eph-ephrin communication within the bone microenvironment. The expression profile of A and B subclass Eph and ephrin molecules and their influence on: (A) chondrogensis and cartilage formation; (B) osteogenic differentiation and mineral formation, (C) adipocyte function within white and marrow adipose tissue; (D) osteoclast formation, differentiation and resorptive function; (E) during the processes of angiogenesis including adhesion, migration, sprouting and intussusceptive “splitting” angiogenesis. The permissive signal is represented in the blue box and the inhibitory response is represented in the red box.

Figure 4

Eph-ephrin contribution to HSC niche maintenance. A schematic demonstrating Eph-ephrin signaling through bone marrow stromal stem cells (BMSC, blue) and sinusoid endothelium to regulate hematopoietic stem/progenitor cell (HPSC, green) maintenance and function.