Osteoclast

Osteoclasts are dome-shaped. They possess a ruffled border, which lies against the bone. Lysosomes fuse and form the ruffled border (centrally). Imagine deep indentations in the plasma membrane of the osteoclast. The osteoclast seals over a Howship lacuna – a pit in the bone surface. This pit forms from bone degradation (resorption). Each osteoclast is heavily populated with nuclei. This machine-like cell forms from the fusion of numerous monocytes/macrophages. It has large numbers of:

• Mitochondria because of multiple high energy processes/factor:
• Support the numerous nuclei.
• Provide ATP for the Vacuolar H+-ATPase at the ruffled border.
• Cytoskeletal activity: cell motility and attachment.
• Pre-osteoclast fusion and osteoclast differentiation.
• Lysosomes, which play a key role in the acidification necessary for bone resorption.

• Consider that in mitochondrial myopathy (mitochondrial dysfunction), bone resorption is impaired.
• Consider that in Paget’s disease, which involves hyperactive osteoclasts, mitochondrial demand is especially high.

A ring-like sealing zone exists at the periphery of the osteoclast, which attaches to the underlying bone. The sealing zone possess, podosomes, which are rich in:

• Actin, a key cytoskeletal component of the sealing zone attachment apparatus.
• Integrins, which bind directly with the underlying bone matrix.

The sealing zones are called “clear zones” because they lack organelles; the cytoplasm is rich with actin filaments and adhesion molecules but “clear” of organelles. Phosphorylated osteopontin (a non-collagenous glycoprotein) on the bone surface provides the attachment site for the sealing zone. It is a ligand for the sealing zone integrins. The phosphate groups facilitate strong ionic bonding with the integrins. The subosteoclastic resorption compartment (aka “resorption lacuna” or “resorption pit”) forms within the Howship lacuna. Carbonic anhydrase provides protons for acidification. Specifically, carbonic anhydrase facilitates the formation of carbonic acid, which then releases protons through spontaneous dissociation Vacuolar H+-ATPase secretes protons (H+) into the subosteoclastic resorption compartment (aka resorption lacuna).

• The resorption lacuna has a pH of roughly 4.5.
• The pH is lowered in this resorption pit as an initial step in bone degradation to demineralize the bone (dissolve the mineral).

Organic bone degradation (osteoid degradation) requires proteases (aka proteinases) that have the capacity to not only break down simple non-collagen proteins but also break-down fibrillar collagen. Lysosomes at the ruffled border produce and release cathepsin K, a particularly important cysteine proteinase (CP), which is active at low pH. Cathepsin K degrades type I collagen, the primary organic component of bone matrix, in the acidic environment of the resorption lacuna. MMPs also play a key role in collagen degradation but their role is less-well elucidated than that of cathepsin K. We can think of them as cleaning up the resorption pit, itself.

• MMP-9 has been shown to play a role separate in pre-osteoclast migration (something entirely separate from the topic of bone resorption).

TRAP contributes to bone degradation by:

• The generation of reactive oxygen species (ROS).
• The dephosphorylation of osteopontin, which releases the sealing zone integrin attachments from their phosphate binding sites on osteopontin. This allows for osteoclast migration.

When blood calcium levels are low, parathyroid hormone (PTH) stimulates osteoblasts to release RANKL, which binds to the RANK receptor on the osteoclast, and triggers osteoclast breakdown of bone. When the blood calcium level is high, parafollicular cells (aka clear (C) cells) release calcitonin, which binds calcitonin receptors on the osteoclast and inactivate it.