Osteocytes and bone tumor niche

Introduction

Osteocytes are terminally differentiated cells of the osteoblast lineage. They are the most abundant cell type of the bone, representing 95% of all bone cells in skeletally mature adult bone tissue [ ]. Osteocytes are considered permanent residents of skeletal tissue, with an estimated half-life of 25 years [ ], whereas osteoblasts survive for up to 3 months and osteoclasts have a life span of only a few weeks. The definition of an osteocyte is descriptive of its location-cells surrounded by mineralized matrix—not its function; as soon as osteoblasts become entrapped in the matrix they produce, they are called osteocytes. Although initially described as passive cells, we now know that osteocytes are multifunctional cells that sense and transduce mechanical forces in bone, and coordinate both bone formation and bone resorption by secreting cytokines that control the activity of osteoblasts and osteoclasts [ , ]. Thus, osteocytes play a crucial role in regulating the dynamic nature of bone and mineral homeostasis. The aim of this chapter is to explore the possible role of osteocytes in malignant bone disease.

Osteocytes: a multifunctional bone cell

A small proportion of osteoblasts will become osteocytes (up to 30%). Most osteoblasts undergo apoptosis whereas others transform into inactive surface lining osteoblasts [ ]. Under certain conditions they may be able to differentiate into cells that produce chondroid bone [ ]. The proportion of osteoblasts that follow each of these fates depends on the animal species, the age and type of bone [ ], and hormonal or disease status [ , ]. Osteocytogenesis has been thought to be a passive process, whereby those osteoblasts on the bone surface that are destined for burial as osteocytes slow down matrix production, and are buried by neighboring osteoblasts that continue to produce matrix actively [ , ]. The process of osteocytogenesis is largely unknown, but the following molecules have been shown to play a crucial role in the production of healthy osteocytes, either in correct numbers or specific distributions: matrix metalloproteinases (MMPs), dentin matrix protein 1 (DMP-1), osteoblast/osteocyte factor 45 (OF45), Klotho, TGFb inducible early gene-1 (TIEG), lysophosphatidic acid (LPA), E11 antigen, and oxygen [ ], and there are several arguments against osteocytogenesis being a passive process. Heterogeneity in osteoblast gene and protein expression patterns has been reported [ ], raising the possibility that subpopulations of osteoblasts may be destined for different fates, based on their gene expression.

A model with eight recognizable transitional stages from the osteoblast to the osteocyte has been proposed [ ]. In the early stage of osteoblast to osteocyte differentiation, osteocytes are called large osteocytes, young osteocytes, or osteoid-osteocytes. These osteocytes are larger than older osteocytes, retain their ability to synthesize collagen, and their cytoplasm is characterized by a well-developed Golgi apparatus. The transformation from motile osteoblast to entrapped osteocyte takes about 3 days, and during this time, the cell produces a volume of extracellular matrix three times its own cellular volume, which results in 70% volume reduction in the mature osteocyte cell body compared to the original osteoblast volume [ ]. The cell undergoes a dramatic transformation from a polygonal shape to a cell that extends dendrites toward the mineralizing front, followed by dendrites that extend to either the vascular space or bone surface [ ]. As the osteoblast transitions to an osteocyte, alkaline phosphatase is reduced, and casein kinase II is elevated, as is osteocalcin [ ]. Finally, mature osteocytes live deep within mineralized bone in small pockets known as lacunae.

Osteocytes have long cytoplasmic processes that run through small channels called canaliculi, establishing a complex and extensive canalicular network in the mineralized bone [ , ]. Molecules such as E11/gp38 and MT1-MMP appear to play a role in dendrite/canaliculi formation, whereas molecules such as destrin and CapG regulate the cytoskeleton. Gap junctions are formed between their processes and the processes of neighboring osteocytes and surface osteoblasts and enable communication between cells. These long processes reach periosteal and endocortical surfaces of cortical bone, as well as the bone marrow surface. Through this lacunar-canalicular system, osteocytes connect among themselves, establish cell-to-cell interactions with cells on the bone surfaces, such as lining cells, stromal cells, osteoblasts, and/or osteoclasts and their precursors, and distribute autocrine/paracrine-secreted factors. Thus, osteocytes are by no means isolated due to their remote location and envelopment in rigid mineralized extracellular matrix.

A general consensus exists that osteocytes are sensitive to mechanotransduction and translate mechanical strain into biochemical signals [ ], influencing the activity of osteoblasts and osteoclasts, which in turn respond by remodeling bone mass according to environmental requirements (Wolff's law) [ , ]. Supporting this notion, targeted deletion of osteocytes impairs the bone anabolic response to mechanical loading [ ]. Osteocytes' response is readjusted in the presence of other bone agents such as hormones and bone factors. Furthermore, osteocytes are fundamental in mineral homeostasis since they respond to changes in ion concentrations and stimulate exchange of ions between bone matrix and extracellular fluid [ ]. The activities of osteoclasts and osteoblasts must be strictly regulated to ensure that bone homeostasis is maintained. Osteocytes are considered the key regulators to maintain this balance [ ]. Recently, signaling pathways by which the osteocyte exerts control over the other bone cells and the potential ways in which these pathways may be exploited therapeutically have been investigated.

The central role of osteocytes in bone remodeling through RANK/RANKL and Wnt pathways