Osteochondroprogenitor cells are progenitor cells that arise from mesenchymal stem cells (MSC) in the bone marrow. They have the ability to differentiate into osteoblasts or chondrocytes depending on the signalling molecules they are exposed to, giving rise to either bone or cartilage respectively. Osteochondroprogenitor cells are important for bone formation and maintenance.
Alexander Friedenstein and his colleagues first identified osteoprogenitor cells in multiple mammalian tissues, before any genetic or morphological criteria were put in place for bone marrow or connective tissues. Osteoprogenitor cells can be identified by their associations with existing bone or cartilage structures, or their placement in the embryo, as the sites for osteogenesis and chondrogenesis are now known. [1]
Osteochondroprogenitor can be found between MSCs and the terminally differentiated osteoblasts and chondrocytes. Via different signalling molecules and combinations the osteochondroprogenitor will differentiate into either osteoblasts or chondrocytes.
Chondrocytes are only present in cartilage where they will produce cartilaginous matrix to maintain the structure. Sox9, L-Sox5 and Sox6 are needed for the osteochondroprogenitor to undergo chondrocytic differentiation. The transcription factor Sox9 can be found in multiple sites in the body (pancreas, central nervous system, intestines) and it is also found in all chondrocyte progenitor cells, suggesting that they are important in chondrogenesis. [3] [4]
Osteoblasts are cells that group together to form units, called osteons, to produce bone. Runx2 (which may also be known as Cbfa1), and Osx (a zinc finger containing transcription factor) are necessary for osteochondroprogenitor cells to differentiate into the osteoblast cell lineage. These factors also have a role in hypertrophic chondrocyte maturation. [3] [5]
β-catenin of the canonical Wnt signalling pathway plays a role in cell fate determination, as it is critical for osteoblastogenesis, and the differentiation of chondrocytes into osteoblasts. Knock out of the entire pathway results in early embryonic death, therefore most research of this nature utilised conditional knockouts of the pathway. [2]
During mandible development, most of it is formed through intramembranous ossification, where endochondral ossification will occur in the proximal region. TGF-β is important for cell proliferation and differentiation during skeletogenesis. During this process, TGF-β can stimulate differentiation into either chondrocytes or osteoblasts via FGF, Msx1, and Ctgf signalling pathways. General gene knock out of the TGF-β resulted in death. Conditional inactivation of TGF-βr2 of osteochondroprogenitor cells in the cranial neural crest resulted in faster osteoprogenitor differentiation and disorganised chondrogenesis. [6]
TGF-β determines and regulates cell lineages during endochondral ossification through Sox9 and Runx2 signalling pathways. TGF-β will act as a stimulator of chondrogenesis, and an inhibitor of osteoblastic differentiation, by blocking the Runx2 factor through Smad3 activation. Sox9 stimulates differentiation into chondrocytes. Sox9 blocked osteochondroprogenitor cells were found to express osteoblast marker genes, reprogramming the cells into the osteoblastic lineage. [6] [7]
Loss of TGF-β signalling will lead to reduced Sox9 activity, but not prevent it completely, suggesting that there must be other factors and signalling pathways regulating Sox9 activity. Once Sox9 activity is lost, differentiation into the osteoblastic lineage dominates. [8]
It is thought that through a combination of biochemical and biophysical stimuli, the uncommitted stem cells of the embryo will undergo differentiation into certain cell lineages. However the exact mechanism and signalling pathways are still unclear. Studies have shown that embryonic stem cells are more mechanosensitive than their differentiated counterparts. During embryonic development mesenchymal cells will form cellular structures known as 'condensations.' These cellular units will then develop into skeletal and other tissues, such as cartilage, tendon, ligament and muscle tissue.[ citation needed ]
Osteoprogenitor cell condensations can aggregate, dissipate or condense depending on the signals present, however these still remain largely unknown. Depending on the different effects, the cellular condensations may differentiate into osteogenic or chondrocytic condensations.[ citation needed ]
The positioning of the osteoprogenitor cell condensations determines the cell lineage before the signalling molecules can. This is due to their positions relative to any epithelial surfaces. Osteoblastic and chondrogenic condensations differ in their biophysical parameters within the embryo. Their distance in relation to the nearest epithelial surface will determine the cell lineage. For example, osteoblastic condensations are closer to epithelial surfaces so they will be exposed to more biophysical and biochemical stimuli due to the proximity and increased cell-epithelial interactions. [2] [9] [10]
The regeneration potential of skeletal progenitor cells declines with age. [11] This reduction of regeneration potential is associated with increased risk of bone fractures with age. Central to reduction of regeneration potential are the skeletal stem progenitor cells since they are responsible for the growth, regeneration and repair of bone tissue. [11] With increasing age the functionality of adult stem cells declines as DNA damages and mutations accumulate. [12]
Deletion of the Trsp gene in osteochondroprogenitor cells results in abnormal bone growth, delayed ossification, chondronecrosis and dwarfism. General Trsp gene deletion is lethal to the embryo. The results of this research was used as a model for Kashin-Beck disease. Kashin-Beck is a result of combinatorial environmentally induced by factors such as: toxic mould, contaminated grains by mycotoxins, and mostly by selenium deficiency, which is necessary for selenoprotein function. The disease has symptoms similar to those resulting from Trsp gene knockout. [13]
Loss of the regulator, Pten, of the Phophatidylinositol3' kinase pathway results in skeletal overgrowth and growth plate dysfunction, due to overproduction of the matrix and accelerated hypertrophic differentiation. [14]
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and enable mobility. Bones come in a variety of shapes and sizes and have complex internal and external structures. They are lightweight yet strong and hard and serve multiple functions.
Cartilage is a resilient and smooth type of connective tissue. It is a semi-transparent and non-porous type of tissue. It is usually covered by a tough and fibrous membrane called perichondrium. In tetrapods, it covers and protects the ends of long bones at the joints as articular cartilage, and is a structural component of many body parts including the rib cage, the neck and the bronchial tubes, and the intervertebral discs. In other taxa, such as chondrichthyans and cyclostomes, it constitutes a much greater proportion of the skeleton. It is not as hard and rigid as bone, but it is much stiffer and much less flexible than muscle. The matrix of cartilage is made up of glycosaminoglycans, proteoglycans, collagen fibers and, sometimes, elastin. It usually grows quicker than bone.
Osteoblasts are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function in groups of connected cells. Individual cells cannot make bone. A group of organized osteoblasts together with the bone made by a unit of cells is usually called the osteon.
An osteocyte, an oblate shaped type of bone cell with dendritic processes, is the most commonly found cell in mature bone. It can live as long as the organism itself. The adult human body has about 42 billion of them. Osteocytes do not divide and have an average half life of 25 years. They are derived from osteoprogenitor cells, some of which differentiate into active osteoblasts. Osteoblasts/osteocytes develop in mesenchyme.
Chondrocytes are the only cells found in healthy cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans. Although the word chondroblast is commonly used to describe an immature chondrocyte, the term is imprecise, since the progenitor of chondrocytes can differentiate into various cell types, including osteoblasts.
Endochondral ossification is one of the two essential pathways by which bone tissue is produced during fetal development of the mammalian skeletal system, the other pathway being intramembranous ossification. Both endochondral and intramembranous processes initiate from a precursor mesenchymal tissue, but their transformations into bone are different. In intramembranous ossification, mesenchymal tissue is directly converted into bone. On the other hand, endochondral ossification starts with mesenchymal tissue turning into an intermediate cartilage stage, which is eventually substituted by bone.
Intramembranous ossification is one of the two essential processes during fetal development of the gnathostome skeletal system by which rudimentary bone tissue is created. Intramembranous ossification is also an essential process during the natural healing of bone fractures and the rudimentary formation of bones of the head.
Ossification in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in the formation of normal, healthy bone tissue: Intramembranous ossification is the direct laying down of bone into the primitive connective tissue (mesenchyme), while endochondral ossification involves cartilage as a precursor.
Chondroblasts, or perichondrial cells, is the name given to mesenchymal progenitor cells in situ which, from endochondral ossification, will form chondrocytes in the growing cartilage matrix. Another name for them is subchondral cortico-spongious progenitors. They have euchromatic nuclei and stain by basic dyes.
Chondrogenesis is the biological process through which cartilage tissue is formed and developed. This intricate and tightly regulated cellular differentiation pathway plays a crucial role in skeletal development, as cartilage serves as a fundamental component of the embryonic skeleton. The term "chondrogenesis" is derived from the Greek words "chondros," meaning cartilage, and "genesis," meaning origin or formation.
Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.
Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene. BMP4 is found on chromosome 14q22-q23.
Runt-related transcription factor 2 (RUNX2) also known as core-binding factor subunit alpha-1 (CBF-alpha-1) is a protein that in humans is encoded by the RUNX2 gene. RUNX2 is a key transcription factor associated with osteoblast differentiation.
Chondroblastoma is a rare, benign, locally aggressive bone tumor that typically affects the epiphyses or apophyses of long bones. It is thought to arise from an outgrowth of immature cartilage cells (chondroblasts) from secondary ossification centers, originating from the epiphyseal plate or some remnant of it.
mir-133 is a type of non-coding RNA called a microRNA that was first experimentally characterised in mice. Homologues have since been discovered in several other species including invertebrates such as the fruitfly Drosophila melanogaster. Each species often encodes multiple microRNAs with identical or similar mature sequence. For example, in the human genome there are three known miR-133 genes: miR-133a-1, miR-133a-2 and miR-133b found on chromosomes 18, 20 and 6 respectively. The mature sequence is excised from the 3' arm of the hairpin. miR-133 is expressed in muscle tissue and appears to repress the expression of non-muscle genes.
An isogenous group is a cluster of up to eight chondrocytes found in hyaline and elastic cartilage.
Transcription factor Sp7, also called osterix (Osx), is a protein that in humans is encoded by the SP7 gene. It is a member of the Sp family of zinc-finger transcription factors It is highly conserved among bone-forming vertebrate species It plays a major role, along with Runx2 and Dlx5 in driving the differentiation of mesenchymal precursor cells into osteoblasts and eventually osteocytes. Sp7 also plays a regulatory role by inhibiting chondrocyte differentiation maintaining the balance between differentiation of mesenchymal precursor cells into ossified bone or cartilage. Mutations of this gene have been associated with multiple dysfunctional bone phenotypes in vertebrates. During development, a mouse embryo model with Sp7 expression knocked out had no formation of bone tissue. Through the use of GWAS studies, the Sp7 locus in humans has been strongly associated with bone mass density. In addition there is significant genetic evidence for its role in diseases such as Osteogenesis imperfecta (OI).
Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells, are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes and adipocytes.
Many human blood cells, such as red blood cells (RBCs), immune cells, and even platelets all originate from the same progenitor cell, the hematopoietic stem cell (HSC). As these cells are short-lived, there needs to be a steady turnover of new blood cells and the maintenance of an HSC pool. This is broadly termed hematopoiesis. This event requires a special environment, termed the hematopoietic stem cell niche, which provides the protection and signals necessary to carry out the differentiation of cells from HSC progenitors. This stem-cell niche relocates from the yolk sac to eventually rest in the bone marrow of mammals. Many pathological states can arise from disturbances in this niche environment, highlighting its importance in maintaining hematopoiesis.
Craniofacial regeneration refers to the biological process by which the skull and face regrow to heal an injury. This page covers birth defects and injuries related to the craniofacial region, the mechanisms behind the regeneration, the medical application of these processes, and the scientific research conducted on this specific regeneration. This regeneration is not to be confused with tooth regeneration. Craniofacial regrowth is broadly related to the mechanisms of general bone healing.