Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit

Abstract

Coupling between bone formation and bone resorption refers to the process within basic multicellular units in which resorption by osteoclasts is met by the generation of osteoblasts from precursors, and their bone-forming activity, which needs to be sufficient to replace the bone lost. There are many sources of activities that contribute to coupling at remodeling sites, including growth factors released from the matrix, soluble and membrane products of osteoclasts and their precursors, signals from osteocytes and from immune cells and signaling taking place within the osteoblast lineage. Coupling is therefore a process that involves the interaction of a wide range of cell types and control mechanisms. As bone remodeling occurs at many sites asynchronously throughout the skeleton, locally generated activities comprise very important control mechanisms. In this review, we explore the potential roles of a number of these factors, including sphingosine-1-phosphate, semaphorins, ephrins, interleukin-6 (IL-6) family cytokines and marrow-derived factors. Their interactions achieve the essential tight control of coupling within individual remodeling units that is required for control of skeletal mass.

Figure 1

Remodeling is initiated within BRCs at points beneath the canopy of cells lining trabecular bone (upper panels) and within cortical bone Haversian canals (lower panels). Osteoclasts (OCs) are formed from hemopoietic precursors (HSC) supplied by marrow and the bloodstream. Precursors of osteoblasts come from MSCs in the marrow, from blood and from pericytes, and differentiate within the BMU through the osteoblast precursor stage to fully functional synthesizing osteoblasts and to osteocytes; lining cells may also differentiate into active osteoblasts. T cells and macrophages can gain access to the BRC from the blood supply (see text for details).

Figure 2

Intercellular communication pathways within the BMU that comprise the remodeling process (see text for details). (1) Stimulatory and inhibitory signals from osteocytes to osteoblasts (e.g. OSM, PTHrP and sclerostin). (2) Stimulatory and inhibitory signals from osteoclasts to osteoblasts (e.g. matrix-derived TGFβ and IGF-1, secreted CT-1, Sema4D and S1P). (3) Signaling within the osteoblast lineage (e.g. ephrinB2 and EphB4, Sema3a, PTHrP, OSM). (4) Stimulatory and inhibitory signals between the osteoblast and osteoclast lineages (e.g. RANKL, Sema3B, Wnt5a and OPG). (5) Marrow cell signals to osteoblasts (e.g. macrophage-derived OSM, T-cell-derived interleukins and RANKL).