Biology Assignment 代写 Osteoclast Differentiation And Its Implications In Osteoporosis
Osteoclasts are derived from haemopoetic stem cells and differentiate from a mononuclear cell into a multinucleate bone-resorbing osteoclast. Many important factors participate in this signalling pathway, such as Macrophage Colony Stimulating Factor (M-CSF), Osteoclast Differentiation Factor (ODF) and Osteoprotegerin (OPG). One of the key mechanisms within the pathway is the interaction between ODF and its receptor-RANK. This leads to a series of signals which further the differentiation and activation of osteoclasts. OPG reduces this interaction by acting as a decoy receptor to ODF. Osteoblasts play a key role in the regulation of this pathway as they secrete M-CSF, ODF and OPG and therefore osteoclastogenesis is dependent on these cells. A variety of other factors and hormones influence the pathway indirectly by stimulating or inhibiting osteoblasts and affecting both their differentiation and activation. Knowledge of the interaction between osteoblasts, osteoclasts and the signalling molecules between them has given rise to a variety of treatments for bone disease but this project focuses on its use in osteoporosis drug therapy and tissue engineering development. Examples of osteoporosis treatment include monoclonal antibodies that target ODF, drugs that increase OPG secretion, or drugs that modulate the activity hormones that suppress the pathway, such as oestrogen. Some drugs work by a combination of mechanisms in addition to inhibiting osteoclast differentiation, such as increasing osteoblasts and bone forming activity and inhibiting reactions involved in the bone resorption process.
New techniques in bone tissue engineering make use of the pathway by culturing osteoclasts together with osteoblasts to form bone tissue substitutes of higher quality compared to those made solely from osteoblasts. Furthermore, studies have recently tried to combine the use of drug therapy with tissue engineering for better delivery of treatment.
Osteoclasts are large, multinucleate bone-resorbing cells which are important in remodelling bone to function more efficiently under certain pressures. They work by releasing hydrogen ions and hydrolytic enzymes such as Cathepsin K which are used to break up the organic content of the bone as well as the hydroxyapatite mineral portion. This mineral matrix contains Calcium and Phosphate ions which are then released into the blood.
Consequently, the regulation of osteoclast activity is very important as an increase in bone resorption will lead to an increase in calcium and phosphate ion concentrations in the blood. This is achieved with hormones such as parathyroid hormone (PTH stimulates osteoclasts indirectly via osteoblasts), Calcitonin (inhibits osteoclast activity) and a number of cytokines such as Interleukins 1 and 6. Studies have shown that these cytokines not only have a positive effect on osteoclast activity but also on their differentiation (Roodman, 1992). This is also the case with other local factors such as Osteoprotegerin (OPG) , Osteoclast differentiation factor (ODF or RANK Ligand) and many others.
Many studies in vitro and on mice have been conducted in order to determine the actions of specific substances which help develop an activated bone-resorbing osteoclast from its haemopoetic precursor. Osteoclasts begin with macrophage characteristics (Kurihara et al, 1990, Hattersley et al, 1991) and are then recruited to the bone surface where these factors play a part in inducing the formation of the osteoclast. In particular, the discovery of the RANK Ligand pathway in the mid 1990’s by Amgen, saw a breakthrough in the understanding of osteoclast formation and the profound therapeutic implications of these substances were realised.
Many bone diseases characterised by excessive bone resorption by osteoclasts, such as osteoporosis or hyperparathyroidism can potentially be treated with knowledge of how to inhibit the pathway. Similarly problems with osteoclasts and the role of RANK in inflammatory diseases such as periodontitis and rheumatoid arthritis have also been studied (Gravallese et al, 2000). Conversely osteopetrosis, a genetic disease resulting in osteoclast dysfunction, could be treated by identifying factors missing from the pathway and replenishing them using gene therapy (Askmyr et al, 2009). Using stem cell transplantation and addition of factors that stimulate osteoclast phenotype acquisition has also been studied in order to develop high quality bone for fractures (Pirraco et al, 2009).
The osteoclast differentiation process and its impact on the pharmacology of drugs used to treat osteoporosis will be looked at in more detail, in addition to more recent studies into its potential in tissue engineering therapeutics for the future.