Osteoclasts: more than 'bone eaters'

Abstract

As the only cells definitively shown to degrade bone, osteoclasts are key mediators of skeletal diseases including osteoporosis. Bone-forming osteoblasts, and hematopoietic and immune system cells, each influence osteoclast formation and function, but the reciprocal impact of osteoclasts on these cells is less well appreciated. We highlight here the functions that osteoclasts perform beyond bone resorption. First, we consider how osteoclast signals may contribute to bone formation by osteoblasts and to the pathology of bone lesions such as fibrous dysplasia and giant cell tumors. Second, we review the interaction of osteoclasts with the hematopoietic system, including the stem cell niche and adaptive immune cells. Connections between osteoclasts and other cells in the bone microenvironment are discussed within a clinically relevant framework.

Keywords: PTH; bone remodeling; osteoblast; osteoclast; osteopetrosis; osteoporosis.

Figure 1. Osteoclasts-osteoblast interactions in the basic multicellular unit (BMU)

A. Osteoclasts (OC) differentiate from OC precursors (OCP) under the influence of MCSF and RANKL produced by osteoblast (OB) lineage cells including osteocytes. As OCs create a resorption pit, growth factors, including TGFβ and IGF1, are released from the bone matrix. These growth factors may recruit mesenchymal osteoblast progenitors and promote their differentiation into mature cells that secrete osteoid to fill the area of resorbed bone. Some OBs differentiate further into matrix embedded osteocytes. B. OCs produce a number of clastokines (see Table 1) that may recruit OB progenitors and promote their proliferation and differentiation. C. Cell-cell contact mechanisms may also mediate OC-OB communication. Bidirectional signaling from OC ephrins and OB Eph receptors and reverse signaling through RANKL on OBs have both been invoked. Abbreviations: MCSF, macrophage colony stimulating factor; RANKL, receptor activator of NF-κB ligand; TGFβ, transforming growth factor β; IGF1, insulin-like growth factor 1.

Figure 2. Immunoregulation by osteoclasts

Osteoclast precursors (OCPs) and osteoclasts (OCs) inhibit CD4 and CD8 T-cell proliferation via nitric oxide (NO) production in response to T-cell derived interferon γ (IFNγ). IFNγ in turn inhibits differentiation of OCPs into mature OCs. OCs also present antigen through major histocompatibility complex Class I (MHCI) to skew CD8+ T-cells toward an induced T_reg phenotype termed OC-iTcreg. OC-iTcreg in turn inhibit OCP differentiation to mature OC through IFNγ, interleukin 10 (IL10) and IL6.