Osteocyte-driven bone remodeling

Abstract

Osteocytes, the most abundant cells in bone, have been long postulated to detect and respond to mechanical and hormonal stimuli and to coordinate the function of osteoblasts and osteoclasts. The discovery that the inhibitor of bone formation sclerostin is primarily expressed in osteocytes in bone and downregulated by anabolic stimuli provided a mechanism by which osteocytes influence the activity of osteoblasts. Advances of the last few years provided experimental evidence demonstrating that osteocytes also participate in the recruitment of osteoclasts and the initiation of bone remodeling. Apoptotic osteocytes trigger yet-to-be-identified signals that attract osteoclast precursors to specific areas of bone, which in turn differentiate to mature, bone-resorbing osteoclasts. Osteocytes are also the source of molecules that regulate the generation and activity of osteoclasts, such as OPG and RANKL; and genetic manipulations of the mouse genome leading to loss or gain of function or to altered expression of either molecule in osteocytes markedly affect bone resorption. This review highlights these investigations and discusses how the novel concept of osteocyte-driven bone resorption and formation impacts our understanding of the mechanisms by which current therapies control bone remodeling.

Figure 1. Osteocytogenesis and osteocyte maturation

(A) Stages of osteocytogenesis and main transcription factors involved in differentiation of osteoblast precursors towards mature osteocytes. (B) Row of osteoblasts (bottom red arrows); an osteocyte recently embedded (top red arrow); two osteocytes completely embedded in osteoid (bottom white arrows); an osteocyte fully embedded in mineralized bone matrix (top white arrow). Picture was contributed by Keith Condon, Indiana University School of Medicine, IN, USA. (C) Morphology of an early osteocyte being embedded in bone; with part of the cell surface partially embedded (left) and the other part totally embedded (right) in mineralized matrix, 10,000 ×, rat bone. Picture was contributed by Stephen B. Doty, Hospital for Special Surgery, New York, NY, USA. (Reprinted with kind permission of Elsevier, Basic and Applied Bone Biology, Chapter 2 Bone Cells, Bellido, Plotkin and Bruzzaniti).

Figure 2. Gene expression at different stages of osteocyte development and maturation

The osteocyte phenotype is characterized by the expression of groups of genes closely related to their morphology and function. Expression of some of these genes changes at different stages of osteocyte development and maturation. Boxes group four main categories: 1) Genes related to dendritic morphology and canaliculi formation; 2) genes related to phosphate metabolism and matrix mineralization; 3) genes that regulate bone formation; and 4) genes that regulate bone resorption. Please, note that several of these genes are also expressed in other cell types, besides cells of the osteoblastic lineage. (Reprinted with kind permission of Elsevier, Basic and Applied Bone Biology, Chapter 2 Bone Cells, Bellido, Plotkin and Bruzzaniti).

Figure 3. Regulation of osteoblast and osteoclast production and function by osteocytes

Osteocytes regulate bone formation through sost/sclerostin. Thus, bone formation induced by systemic elevation of PTH or local mechanical loading is associated with decreased expression of sclerostin. Osteocytes regulate bone resorption through pro- and anti-osteoclastogenic cytokines. Resorption under basal conditions, induced by PTH elevation or by PTHrP increased during lactation is regulated by RANKL through the PTH receptor (PTHR) expressed in osteocytes. Activation of Wnt signaling in osteocytes increases OPG expression leading to inhibition of resorption. Osteocyte apoptosis induced by immobilization, fatigue loading, sex steroid deficiency, or genetically induced by activating diphtheria toxin receptor signaling, is sufficient to recruit osteoclasts to specific bone areas and increase resorption; likely through a mechanism that increases RANKL expression in still-living osteocytes surrounding dead osteocytes. (Reprinted with kind permission of Elsevier, Basic and Applied Bone Biology, Chapter 2 Bone Cells, Bellido, Plotkin and Bruzzaniti).

Figure 4. Osteocytes and the bone remodeling compartment (BRC)

Apoptotic osteocytes might initiate bone remodeling by sending signals to lining cells, which retract from the bone surface to form a structure named the bone remodeling compartment (BRC). Osteoclast precursors are transported to the BRC by marrow capillaries, differentiate to mature osteoclasts under the influence of pro- and anti-osteoclastogenic cytokines (RANKL, M-CSF and OPG) derived from osteocytes, and initiate bone remodeling. Osteoblast precursors from the bone marrow or the circulation differentiate into mature, bone synthesizing cells in response to factors released from the bone matrix by resorption. Differentiation and function of osteoblasts is controlled by molecules derived from osteocytes, including sclerostin and Dkk1. (Reprinted with kind permission of Elsevier, Basic and Applied Bone Biology, Chapter 2 Bone Cells, Bellido, Plotkin and Bruzzaniti).