Roles of osteoclasts in alveolar bone remodeling

Abstract

Osteoclasts are large multinucleated cells from hematopoietic origin and are responsible for bone resorption. A balance between osteoclastic bone resorption and osteoblastic bone formation is critical to maintain bone homeostasis. The alveolar bone, also called the alveolar process, is the part of the jawbone that holds the teeth and supports oral functions. It differs from other skeletal bones in several aspects: its embryonic cellular origin, the form of ossification, and the presence of teeth and periodontal tissues; hence, understanding the unique characteristic of the alveolar bone remodeling is important to maintain oral homeostasis. Excessive osteoclastic bone resorption is one of the prominent features of bone diseases in the jaw such as periodontitis. Therefore, inhibiting osteoclast formation and bone resorptive process has been the target of therapeutic intervention. Understanding the mechanisms of osteoclastic bone resorption is critical for the effective treatment of bone diseases in the jaw. In this review, we discuss basic principles of alveolar bone remodeling with a specific focus on the osteoclastic bone resorptive process and its unique functions in the alveolar bone. Lastly, we provide perspectives on osteoclast-targeted therapies and regenerative approaches associated with bone diseases in the jaw.

Keywords: alveolar bone; bone remodeling; bone resorption; jawbone; mechanical stress; osteoclast; periodontitis.

FIGURE 1

Schematic representation of alveolar bone development. The enamel organ, dental papilla, and dental follicle constitute the tooth germ and give rise to the essential structures of the tooth and supporting tissues: the enamel, dentin–pulp complex, and periodontium including cementum, periodontal ligament (PDL), and alveolar bone, respectively (a). The alveolar bone (alveolar process) rests on the basal bone of the mandible and maxilla, and consists of alveolar bone proper and supporting bone. The trabecular bone is located between alveolar bone proper and plates of cortical bone (b). Sharpey's fibers are bundles of PDL collagen fibers embedded in the alveolar bone proper and cementum at a right angle (c)

FIGURE 2

Schematic representation of osteoclast origin and differentiation. The hematopoietic stem cells (HSCs) give rise to common myeloid progenitors (CMPs) and differentiate into granulocyte/macrophage progenitors (GMPs) by stimulation with granulocyte/macrophage stimulating factor (GM‐CSF). GMPs further differentiate into monocytes/macrophage lineage by M‐CSF stimulation and become osteoclast (OC) progenitors. OC progenitors enter the blood circulation and migrate toward bone surfaces where they fuse and become multinucleated osteoclasts upon stimulation with M‐CSF and receptor activator of NF‐κB ligand (RANKL). Activated mature osteoclasts resorb bone matrix and undergo either apoptosis or recycling via osteomorphs (a). During embryonic development, yolk sac erythroid–myeloid progenitors (EMPs) differentiate into OC progenitors and become multinucleated osteoclasts. In postnatal life, these precursors are gradually replaced by HSC‐derived OC progenitors that fuse with EMP‐derived osteoclasts (b)

FIGURE 3

Schematic representation of bone resorption by osteoclasts. Activated osteoclasts form the sealing zone that surrounds the ruffled border and defines the area of bone surface to be resorbed. During bone resorption, H⁺ (protons) and chloride ions are transported through the Vacuolar H⁺‐ATPase and chloride channel localized on the ruffled border, respectively. Degradation of bone matrix is mediated by enzymes such as cathepsin K and tartrate‐resistant acid phosphatase (TRAP). Matrix degradation products are endocytosed from the ruffled border and released from the functional secretory domain (a). Osteoclasts resorb bone in two different modes: the intermittent and stationary resorption mode resulting in rounded resorption cavities termed pits, and the continuous resorption mode where the osteoclast moves during resorption resulting in deep elongated cavities termed trenches (b)

FIGURE 4

Schematic representation of cellular interactions between osteoclasts, osteoblasts, and osteocytes in bone remodeling. Osteoblasts and osteocytes express RANKL and osteoprotegerin (OPG). RANKL binding to RANK receptor on the osteoclasts leads to differentiation and activation of osteoclasts. OPG acts as a decoy receptor for RANKL and thus inhibits osteoclast differentiation. Osteocytes inhibit bone formation and promote bone resorption via Sclerostin (SOST). Osteoclasts regulate migration and activity of osteoblasts through factors secreted from osteoclasts themselves and bone resorption cavities

FIGURE 5

Schematic representation of alveolar bone remodeling during mastication. Mechanostat model of functional adaptation of bone. Above the certain threshold levels for strain, bone formation modeling which is independent of bone resorption occurs to increase bone mass. A lower than the certain threshold level for strain leads to increased bone remodeling and resorption, resulting in decreased bone mass. In the normal loading range, bone formation and bone resorption are balanced, and total bone mass is unchanged (a). Sclerostin (SOST) and DKK1 inhibit osteoblast differentiation and stimulate osteoclastogenesis. Lower mechanical loading results in osteocyte apoptosis and increases in sclerostin production, leading to increased bone resorption. Higher mechanical loading by occlusal forces during mastication reduces sclerostin production from osteocytes, which decreases bone resorption and accelerates new bone formation in the alveolar bone (b)

FIGURE 6

Schematic representation of alveolar bone remodeling during orthodontic tooth movement. The compressed side of PDL is called the compression side and the side where the PDL is pulled is called the tension side. Osteoclasts resorb bone matrix on the compression side to create space for tooth movement, while new bone formation occurs at the tension side. During orthodontic tooth movement, RANKL, IL‐1β, TNF‐α, and prostaglandin (PG)E2 secreted from cells in the PDL or osteocytes on the compression side control osteoclastic bone resorption, while OPG, TGF‐β, IL‐10, and sclerostin (SOST) on the tension side control osteoblastic bone formation