Biological regulation of bone quality

Abstract

The ability of bone to resist fracture is determined by the combination of bone mass and bone quality. Like bone mass, bone quality is carefully regulated. Of the many aspects of bone quality, this review focuses on biological mechanisms that control the material quality of the bone extracellular matrix (ECM). Bone ECM quality depends upon ECM composition and organization. Proteins and signaling pathways that affect the mineral or organic constituents of bone ECM impact bone ECM material properties, such as elastic modulus and hardness. These properties are also sensitive to pathways that regulate bone remodeling by osteoblasts, osteoclasts, and osteocytes. Several extracellular proteins, signaling pathways, intracellular effectors, and transcription regulatory networks have been implicated in the control of bone ECM quality. A molecular understanding of these mechanisms will elucidate the biological control of bone quality and suggest new targets for the development of therapies to prevent bone fragility.

Figure 1. Perilacunar Remodeling by Osteocytes

Bone health is maintained through dynamic remodeling executed by osteoclasts, osteoblasts, and osteocytes. While osteocytes direct osteoclast and osteoblast activity, osteocytes also play a direct role in remodeling bone matrix. Through a dynamic process called perilacunar remodeling (PLR), osteocytes secrete protons and proteases to resorb the perilacunar bone matrix, often to accommodate metabolic demands. After mineral homeostasis is restored, osteocytes refill the lacunar spaces with new bone matrix. Several osteocyte-derived proteins have been implicated in PLR including cathepsin K, MMP13, MT-1MMP, MMP2, TRAP, the Na/H+ exchanger, but not the osteoclast marker, RANK. Recent studies using genetically modified mice demonstrate that MMP13-dependent PLR is an essential constitutive process that actively maintains bone quality.