What Is an Osteoclast?

Osteoclast (OC) is the main functional cell for bone resorption, and plays an important role in bone development, growth, repair, and reconstruction. Osteoclasts originate from the blood mononuclear-macrophage system, which is a special terminally differentiated cell. It can be fused by its mononuclear precursor cells in many ways to form huge multinucleated cells.

Chinese name: Osteoclasts
Foreign name: osteoclast

Nature: A component of bone tissue
Function: Exercise bone resorption

The evolution of osteoclasts

Osteoclasts are composed of multi nuclear giant cells (MNGC), with a diameter of 100 m, containing 2 to 50 closely packed nuclei, which are mainly distributed on the surface of bone and around blood vessels in bone. Fusion of multiple monocytes, basophilic cytoplasm but gradually eosinophilic as cells age.

Isolation and culture of osteoclasts began in the 1980s. Until July 2018, the main methods of osteoclast culture are: bone marrow mechanical separation, bone marrow cell induction, spleen stem cell induction, and blood mononuclear cell induction. Induction of mouse RAW264.7 cell line and isolation of giant cell tumor of bone.

Osteoclast source

Osteoclasts are multinucleated giant cells formed by the fusion of mononuclear macrophages differentiated from myeloid progenitor cells in the bone marrow. Early immature proliferating mononuclear phagocytic cells are called precursors of osteoclasts, enter the blood circulation under the action of chemical factors, and then enter the cavity of bone structure under the action of signal factors released by basal multicellular units. Stimulated by various chemical factors, transcription factors, cytokines and other signal factors, they fused into multinucleated cells and eventually activated into osteoclasts.

Osteoclast apoptosis

Osteoclast apoptosis is controlled by two different signaling pathways, one is initiated by death receptors (tumor necrosis factor receptor family, which contains intracellular death domains), and one is regulated by Bcl-2 family proteins. Both pathways can activate caspase, which can induce apoptosis by cleaving specific substrates.

In the process of osteoclasts absorbing the organic matter and minerals of the bone matrix, the surface of the matrix is irregular, and a pit with an approximately cell shape is formed, which is called Howship pit. On the side facing the bone in the pit, the cells protruded with many hair-like protrusions, much like the longitudinal edges and bristle edges of the epithelial cell surface. Under the electron microscope, there are many irregular microvilli on the side close to the bone, that is, cell protrusions, called ruffled borders. There is a circular cytoplasmic area around the wrinkled marginal zone, containing a large amount of microfilaments, but lacking other organelles, called the clear zone, where the cell membrane is flat and clings to the surface of bone. The bright area is like a wall made of cytoplasm, which forms the surrounding area into a micro-environment.

Osteoclast process

Osteoclasts release lactic acid and citric acid to the local area. Under acidic conditions, inorganic minerals in the bone swallow from the wrinkle margin, forming some swallowing bubbles or phagocytosis in the wrinkle margin matrix. In osteoclasts, minerals are degraded and excreted into the bloodstream in the form of calcium ions. The loss of inorganic matter exposes the collagen fibers in the bone matrix, and osteoclasts secrete a variety of lysosomal enzymes, especially cathepsin K and collagen solubilizing cathepsin. After osteoclasts leave the bone surface, their fold edges disappear, intracellular changes occur, and they enter a stationary phase.

Osteoclast

Osteoclasts are known for their bone resorption function. Furthermore, as a component of bone tissue, it functions as a bone resorption. Osteoclasts and osteoblasts (also known as bone-forming cells) correspond functionally. The two work together to play an important role in the development and formation of bones. Highly expressed tartrate resistant acid phosphatase and cathepsin K are the main markers of osteoclasts.

But beyond that, osteoclasts have other biological effects. By July 18, the effects of hematopoiesis, bone formation, bone angiogenesis, and osteocalcin were found. Osteoclasts have a special absorption function. Macrophages also participate in the process of bone resorption in the absorption of certain local inflammatory lesions.

Clinical prospects of osteoclast research

Abnormal osteoclast function can cause abnormal bone resorption. If it is hyperfunctional, it can cause bone degenerative diseases such as osteoporosis, cancer bone metastasis, arthritis, etc .; if its dysfunction or regression, it can cause bone sclerosis Disease, compact osteogenesis imperfecta, Paget's disease, massive osteolysis disease, etc.

Drugs for bone-related diseases mainly affect the bone resorption process from three aspects: differentiation, function and apoptosis of osteoclasts. Because the RANK / RANKL / OPG axis has a key regulatory significance for the formation and absorption of bone, many studies today focus on the role of this axis. Inhibition of RANKL can be used as an ideal treatment strategy for excessive bone resorption, such as recombinant osteoprotectin, all human anti-RANKL blocking antibodies, and RANK-Fc can effectively block RANKL and bone resorption in clinical trials. However, whether long-term use will have adverse effects on tissues and the immune system is still unknown, so it is still in the research stage. Bisphosphonates have a high affinity for bone matrix and can induce osteoclast apoptosis.

There are also reports that long-term bisphosphonates can cause femoral fractures, and intravenous bisphosphonates or denosumab (RANKL monoclonal antibody) can cause joint osteonecrosis. The bisphosphonate derivative of enoxacin has the function of selectively inhibiting osteoclasts. Because it does not affect the osteoclast-specific protein expression concentration, it can inhibit osteoclast-dependent orthodontic tooth movement. Some scholars have suggested that cathepsin K can be used to block the process of bone resorption. The study of osteoclast signaling pathway provides a new direction for the development of new drugs targeted to block the differentiation and function of osteoclasts: RANKL participates in the process of osteoclast formation and differentiation in diseases such as myeloma, large cell carcinoma of bone, The RANK / RANKL pathway can prevent the osteoclast differentiation process, prevent bone resorption, maintain bone density, and reduce the risk of fracture. During bone resorption, osteoclasts secrete proteinase K extracellularly, and gene knockout or blocking cathepsin K will hinder the process of bone resorption, which will also be a new direction of drug research. Some scholars have proposed that by studying the nuclear receptors of osteoclasts, these precise metabolic sensors can be targeted to regulate and control the occurrence of related diseases at the molecular level. The transcription factor FBI-1 / OCZF / LRF can regulate the formation and apoptosis of osteoclasts. The regulation of this transcription axis is expected to treat chronic arthritis and reduce bone loss. The influence of age should not be ignored in the study of bone tissue homeostasis. Increasing age will promote the accumulation of pro-inflammatory factors, enhance the role of myeloblasts and osteoclasts, which will inspire research on related diseases and drug development. During the process of osteoclasts absorbing the bone matrix, part of the growth factors released can affect the differentiation and activity of osteoblasts, so it is also possible to understand the relevant mechanism of bone formation by studying osteoclasts. The role of immune cells in the process of osteoclast formation is very complex. The formation of osteoclasts also affects lymph node formation, B cell maturation, and immune response. This has led to bone immunology, its complex mechanisms and related diseases The research is in full swing. The presence of osteoclasts in the primary cancer lesions suggests that the survival of osteoclasts does not only depend on bone tissue. In addition to studying the treatment of bone diseases from osteoclasts, it may also be related to other systems by studying The relationship between disease occurrence and development provides new ideas and new approaches for future treatment. Absorbable biomaterials can unify the process of osteoclast formation and bioabsorption, and studying the functional mechanism of osteoclasts in it also has considerable prospects for tissue engineering.