The 4 types of Bone Cells
Having examined the inorganic and organic components that constitute bone material, as well as the histologically distinct structures of compact and spongy bone, we now turn our attention to the four types of bone cells responsible for breaking down, forming, and continuously maintaining bone. These include osteoclasts, osteoblasts, osteocytes, and lining cells. Though they make up less than 2% of total bone mass, these cells are the true creators and caretakers of the mineralized extracellular matrix that constitutes the rest of the bone.
Origin of Osteoclasts
Osteoclasts are large, multinucleated cells responsible for bone resorption and remodeling, playing a vital role in calcium homeostasis. They originate from the monocyte/macrophage lineage of hematopoietic stem cells (HSCs). These HSCs first differentiate into common myeloid progenitors (CMPs) in the bone marrow, and then, under the influence of the hematopoietic growth factor M-CSF (macrophage colony-stimulating factor), develop into CFU-GM (colony-forming unit–granulocyte/macrophage) and monocyte precursors. From there, they become osteoclast precursors, a cell type closely related to macrophages and monocytes. When the osteoblast-secreted RANKL (receptor activator of nuclear factor-κB ligand) binds to the RANK receptor expressed on the surface of these precursors, they begin to differentiate into osteoclasts. Subsequently, multiple mononuclear osteoclast precursors fuse together to form large, multinucleated mature osteoclasts, which then start bone resorption.
Origin of Osteoblasts
Osteoblasts, the functional counterparts of osteoclasts, synthesize bone matrix and promote mineralization. They derive from mesenchymal stem cells (MSCs), which are found in the bone marrow, periosteum, and connective tissues, and are capable of differentiating into various cell types including adipocytes, chondrocytes, and myocytes. Differentiation into osteoblasts is induced by signals from bone morphogenetic proteins (BMPs), part of the transforming growth factor-beta (TGF-β) family, the Wnt/β-catenin signaling pathway, and activation of Runx2, a critical transcription factor for osteogenic differentiation. As osteoclasts break down the bone matrix and release hydrogen ions, they create a localized acidic environment. This causes latent growth factors like TGF-β and IGF-1 (insulin-like growth factor 1), which had been embedded in the bone matrix, to be released and activated. These factors act as chemotactic signals to guide mesenchymal stem cells toward osteoblastic differentiation.[1] MSCs first become osteoprogenitor cells, then pre-osteoblasts, and finally mature osteoblasts. These mature cells secrete growth factors that bind to their own receptors (autocrine signaling) or stimulate nearby MSCs and pre-osteoblasts (paracrine signaling), reinforcing and promoting osteogenic differentiation.
Once osteoblasts have completed their role in bone formation, they follow one of three possible fates: they become embedded in the matrix they secreted and differentiate into osteocytes to monitor and regulate the bone internally, they transform into lining cells that cover the bone surface, or they undergo apoptosis to maintain balance between bone formation and resorption. Interestingly, osteoblasts and osteoclasts mutually regulate each other’s differentiation. Osteoclast activity stimulates osteoblast differentiation, while osteoblasts secrete RANKL to induce osteoclast formation. This reveals a tightly coordinated interplay between the two cell types.
Osteocytes
Osteocytes are the final differentiated form of osteoblasts, arising from those that have completed bone formation. They constitute approximately 85–90% of all bone cells and have a long lifespan. As osteoblasts secrete bone matrix and bury themselves in it, they gradually change their shape and differentiate into osteocytes. During this process, they lose their secretory function and develop long dendritic processes that connect them with neighboring osteocytes, osteoblasts, lining cells, and nearby blood vessels, forming an extensive communication network. These star-shaped cells reside in small cavities called lacunae and extend their processes through narrow canals known as canaliculi, which allow for signal transmission and nutrient exchange with cells.
Osteocytes possess the ability to detect physical stimuli such as mechanical pressure on the bone and convert them into biochemical signals that trigger bone resorption or formation. For instance, when mechanical stress is applied to the bone, osteocytes sense it and promote osteoblast activity. Conversely, when mechanical loading is reduced, they increase the expression of signals like RANKL to activate osteoclasts and stimulate bone resorption. If microscopic damage occurs to the bone, the resulting changes in bone fluid composition and decreased oxygen levels trigger apoptosis in the affected osteocytes. Surrounding osteocytes then release cytokines such as TNF-α, IL-6, and IL-11 to induce osteoclast differentiation and remove the damaged area.
Osteocytes also play key roles in mineral metabolism by secreting hormones like FGF-23 to regulate phosphate homeostasis, and by suppressing the secretion of sclerostin in response to parathyroid hormone (PTH), thereby enhancing osteoblast activity. In this way, osteocytes are not simply cells trapped in the bone, but highly specialized sensory-regulatory cells that delicately regulate bone structural changes and systemic metabolism.
Lining Cells
Lining cells are the inactive form of osteoblasts that remain after bone formation is complete, covering the surface of the bone in a thin, flattened layer. These cells generally protect the bone surface after the formation process is paused, marking what is known as the resting phase of bone. They interact directly with osteocytes via signaling pathways. When osteocytes release RANKL, lining cells join together to form a structure called the “canopy,” demarcating a remodeling area. At this stage, lining cells loosen their intercellular junctions to allow osteoclasts access to the matrix surface. While they remain in a resting state covering the quiescent bone surface, they can be transformed back into osteoblasts that form bone in response to mechanical stimulation or stimuli such as parathyroid hormone (PTH). [2]
What is Bone Remodeling and Why Does It Occur?
During growth, children experience bone modeling, a process by which bones grow and their shape or structure changes. However, in adults, such modeling mostly ceases, and the bones go through a lifelong, continuous remodeling process, in which the external shape remains largely unchanged while the internal bone is constantly replaced. Bone cells that compose bone tissue communicate and interact closely with each other in a highly organized manner, coordinating their actions to maintain tissue integrity. Through their self-renewal capacity, bones are able to recover from microdamage that occurs daily, as well as from more serious damage caused by fractures, trauma, or disease. Remarkably, bone tissue also has mechanisms to recognize and accept artificially inserted biomaterials.
Remodeling involves breaking down existing bone and forming new bone. In adults, bone resorption in the remodeling region takes about three weeks, while bone formation takes about three to four months. Thus, approximately 5–10% of the skeleton is replaced each year through remodeling. Therefore, the entire adult skeleton is essentially replaced every 7–10 years. Even after the age of 50, remodeling continues within the skeleton to repair damaged bone and remove old bone, but as we age, the amount of bone removed increases while the amount of newly formed bone decreases or the speed of new bone formation decreases, so the balance between bone resorption and bone formation is broken, and even if bone damage is recovered, the total amount of bone decreases, causing bone loss and making it easier for phenomena such as osteoporosis to appear.
Physiological Remodeling and Pathological Remodeling
The initiation of bone remodeling can be divided into two categories. There is remodeling that occurs as part of normal bone metabolism, and remodeling that occurs as a result of external damage under abnormal circumstances. The former is physiological remodeling, which replaces microdamaged or aged bone continuously, while the latter may be termed traumatic or pathological remodeling, which is initiated by physical damage or pathological causes such as fractures, infections, inflammation, or surgery.
Physiological remodeling may begin when osteocytes, which serve as sensors constantly monitoring the condition of the bone, detect mechanical stress or damage and undergo programmed cell death (apoptosis). As osteocytes die, they release apoptotic bodies rich in RANKL, a key signaling protein that activates osteoclasts. (RANKL will be discussed in detail in the section on osteoclasts.) Bone lining cells that detect the osteocyte’s apoptotic signal cover the affected area and form what is called a "canopy" or cellular cover. The local area where remodeling takes place is known as the bone remodeling compartment (BRC), and this canopy, formed by lining cells, shields the BRC from the external environment while allowing signal transmission from blood vessels and immune cells. Think of the canopy as a tent or tarp used in camping to avoid rain, or like a safety enclosure at a construction site to block dust and danger and ensure work proceeds safely inside. Within this canopy, osteoclasts carry out bone resorption.
On the other hand, pathological remodeling involves an accompanying inflammatory response. A large number of immune cells rush to the site of damaged blood vessels and destroyed tissue, releasing inflammatory cytokines such as IL-1, IL-6, and TNF-α, which attract many osteoclasts. This is because a much greater recruitment of osteoclasts is needed than in physiological remodeling. In traumatic situations, inflammation and tissue destruction occur very rapidly, so the canopy structure either forms late or does not form at all.
Physiological remodeling is a slow and precise process, whereas remodeling caused by injury involves widespread cell death and inflammation. To promote rapid healing, large numbers of osteoclasts and osteoblasts are quickly differentiated and mobilized, and immune cells and inflammatory cytokines act strongly to accelerate the rate of bone regeneration.
Bone: A Calcium Reservoir
There is another very important reason for physiological remodeling, unrelated to bone structural maintenance — the homeostatic regulation of calcium (Ca²⁺) concentration in the body. When studying how the human body functions at the cellular level, one realizes how vital calcium is and that it often goes underappreciated. Calcium is central to muscle contraction and relaxation. Muscles move as calcium enters and exits the cells. If calcium concentration in heart cells is too high, contraction strength increases; if it’s too low, contraction decreases. The heart beats properly only when calcium levels are maintained. Calcium is also essential for blood to clot, as it acts as a cofactor in the coagulation process. It changes the 3D structure of proteins to activate enzymes, and it acts as a secondary messenger in many intracellular signaling pathways. Thus, for the body to function normally, appropriate calcium levels must be ensured. Although we often associate calcium with bones, its role is far broader and more critical.
Calcium is primarily found in bones and teeth and about 99% of calcium in the body exists mainly in the form of hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂). The remaining 1% is found in blood, muscles, and intracellular or extracellular fluids. The parathyroid glands are the master regulators of calcium levels. These four small, pea-sized glands behind the thyroid in the neck detect blood calcium levels via calcium-sensing receptors (CaSR) on their cell membranes. If calcium is low, the parathyroid gland secretes parathyroid hormone (PTH), which stimulates osteoblasts to increase RANKL expression and suppresses the production of OPG (osteoprotegerin), a protein that inhibits osteoclast differentiation. Since osteoclasts do not have PTH receptors, bone resorption is induced via this indirect pathway. This causes mineralized bone to get degraded and release calcium ions into the bloodstream.
In addition, PTH reduces phosphate reabsorption and increases calcium reabsorption in the kidneys. It also promotes the synthesis of active vitamin D in the kidneys, enhancing calcium absorption in the intestines. When calcium levels return to normal, PTH secretion is inhibited. Conversely, if blood calcium levels are too high, calcitonin secreted from the thyroid inhibits osteoclasts and increases calcium excretion by the kidneys. These mechanisms work in harmony to maintain precise calcium homeostasis in the body.
This sophisticated physiological regulation system utilizes bone as a calcium reservoir when needed, ensuring the maintenance of systemic physiological functions. When calcium intake from external sources is insufficient, mobilizing calcium from bone is like extracting essential resources from a mine — a survival strategy.
The 5 Stages of Bone Remodeling
Now that we’ve examined the reasons for bone remodeling, let’s look into the detailed process of bone remodeling, which is typically divided into five main stages:
1. Activation: recruitment of osteoclast precursors to the damaged bone surface.
2. Resorption: mature osteoclasts break down and resorb the damaged bone.
3. Reversal: a transitional phase in which osteoclasts undergo apoptosis and osteoblast precursors are recruited.
4. Formation: mature osteoblasts form new bone matrix (osteoid), which then undergoes mineralization.
5. Resting Phase: a period of relative inactivity before the next remodeling cycle.
The overall bone remodeling process can be broadly illustrated as below.
In the following article, we will examine each stage in greater detail.
[References]
[1] Regulation of postnatal bone homeostasis by TGFβ
doi: 10.1038/bonekey.2012.255
[2] The reversal phase of the bone-remodeling cycle: cellular prerequisites for coupling resorption and formation
doi: 10.1038/bonekey.2014.56
Physiology, Parathyroid Hormone
https://www.ncbi.nlm.nih.gov/books/NBK499940/
