Abstract-
In order to study the gene mutation that is supposed to cause Paget’s Bone Disease researchers had to have viable candidates to host the gene mutation. They found the best candidate to host the gene mutation in mice so they implanted the gene mutation in embryos of mice offspring. The researchers hypothesized that p62P394L is sufficient to induce PDB, especially since the p62 gene is responsible for encoding 62 kDa protein which functions in signaling osteoclast precursors. Results were found by fixing the first through fifth lumbar vertebra of four, eight, and twelve month old homozygote, heterozygote and WT littermates in 10% buffered formalin for 24- 48 hours. The first through fourth vertebra were then completely decalcified while the fifth was not. Longitudinal sections of both decalcified and undecalcified vertebra were cut, mounted on glass slides and stained to analyze. The mice with p62P394L had histologically normal bones, indicating that p62 mutation is not enough to induce Paget’s disease of the bone in vivo, there are additional factors necessary. Knowing osteitis deformas is due to hyper responsive multinucleated osteoclasts, it seemed a sensible suggestion. However, there are many other variables that should be factored when considering possible causes for osteoclast hyperformation. If p62P349L is present, doesn’t necessarily mean a person will get PDB, though an environmental factor such as measles could easily open up transduction pathways that could eventually lead to pagetic bone lesions. We find this study to be a stepping stone for future researchers to use in order to actually identify what causes Paget’s bone disease. (Hiruma, Kurihara, Subler, Zhou, Boykin, Zhang, Ishizuka, Dempster, Roodman & Wi...
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...ll understood simply because of the numerous genetic and environmental factors possible in causing any part of PDB, either by over stimulating osteoclast precursors, genetic mutations, producing transduction pathways that would otherwise not be present or even signals misfiring or over active parathyroid gland. Much more isolated research is necessary before this disease can be fully understood.
Works Cited
Hiruma, Y., Kurihara, N., Subler, M., Zhou, H., Boykin, C., Zhang, H., et al. (2008). A SQSTM1/p62 mutation linked to Paget’s disease increases the osteoclastogenic potential of the bone microenvironment. Human Molecular Genetics, 17(23), 3708-3719. Retrieved June 12, 2010, from the PubMed database.
Ooi, C., & Fraser, W. (1997). Paget's disease of bone. The Fellowship of Postgraduate Medicine, 73, 69-74. Retrieved June 12, 2010, from the PubMed database.
An osteoblast is a “baby” bone cell whose main job is to secrete osteoid which forms the hardened, or calcified, bone matrix. Osteocytes are formed from osteoblasts. Osteocytes are the mature bones cells that have been completely differentiated. They are found in the lacunae of hard bone and have a spider-like appearance due to their canaliculi. Osteoclasts are a different type of cell formed from the mesenchymal cells. These cells are not related to osteoblasts or osteocytes. Their job is to basically “eat” the bone to create cavities and other hallow spaces during bone remodeling. Finally, the cells form differentiate to form fibroblasts and fibrocytes. These fibroblasts and fibrocytes secrete and form the matrix for fibrous connective tissue which is an essential component of the
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder (Kartal-Kaess et al., 2010). This means that the disorder is hereditary; an individual can only get the disorder if one of the parents has it and passes it on to the offspring. The main characteristic of this disorder is the hardening of skeletal muscles, connective tissue, tendons, and ligaments (Kartal-Kaess et al., 2010). The skeletal muscles, connective tissue, tendons and ligaments start to progressively become bone. Skeletal muscles, connective tissue, tendons and ligaments are places where bone does not grow in regular individuals that do not have FOP. Other characteristics of FOP include benign tumor composed of bone and cartilage in the tibia, abnormal growth on the cervical spine, wide and small femoral necks and hearing loss (Kartal-Kaess et al., 2010).
Achondroplasia (ACH) is the most common form of short-limb dwarfism occuring in 1 in 15,000 to 28,000 births and appears to be slightly more prevalent in females, but indiscriminent toward race (1-3). Evidence has been found in Egypt for cases of ACH dating back as far as 4500 B.C. (4). In simplest terms, ACH is a disease where the dwarfing of bones formed in the cartilage occurs (5). There are many features that accompany this disease including rhizomelic (proximal) shortening of the extremities, megalencephaly (enlarged brain), short stature, trident hand, and frontal bossing (prominent forehead) (1, 3, 4, 6-8). Expression of this gene at high levels is primarily found in cells of the nervous system and the cartilage rudiments and chondrocytes in the growth plates of developing bone (7, 9). Due to the fact that there are numerous types of skeletal dysplasia, some which appear similar to ACH at times, the only way for complete confirmation is to perform molecular techniques such as genetic testing (1, 4, 8).
(Binder, 386). Other collagen-containing extraskeletal tissues, such as the sclerae, the teeth, and the heart valves are also affected to a variable degree. OI has a "common feature of bony fragility associated with defective formation of collagen by osteoblasts and fibroblasts." (Smith, 1983, 13) This disease, involving defective development of the connective tissues, is usually the result of the autosomal dominant gene, but can also be the result of the autosomal recessive gene. Spontaneous mutations are common and the clinical presentation of the disease remains to be quite broad. (Binder, 386)
The resorption and formation of bone happens with two bone cells and they are the osteoblasts and the osteoclasts (Rucci 2008, p. 49). Osteoblasts are the cells, which are involved with the secretion of the organic and nonorganic components of the bone, and allows for the formation of new bone to occur in the bone-remodelling phase, the osteoclasts is the bone cell which inhibits the formation of new bone and allows for the healing process of the bone to occur (Porth 2012, pp. 1086 - 1087). The complications that can our in the remodelling and healing phase is that bone could be lost and other skeletal disorders can arise such disorders as osteoporosis and they could have a deficit in the connection of the bone marrow function (Rucci 2008, p. 49).
Singer FR. Evolution of the clinical presentation of Paget’s disease of bone. Clin Rev Bone Miner Metab. 2002; 1(2): 95-98.
...the effect of a lack of lymphocytes on fracture repair They used eight week old male recombination activating gene 1 knockout (RAG -/-) mice to model the absence of lymphocytes and wilt-type mice Unilateral closed fractures were induced in all rats and the progression of fracture healing was evaluated at days three, seven, fourteen, twenty-one and twenty-eight The results of the experiment show that during fracture healing the biochemical properties, mineralisation and remodelling were all enhanced in RAG-/- mice Therefore there must be a regulatory role of lymphocytes during fracture repair
Diagnosis of osteonecrosis of femoral head is done clinically by pain around the hip, gradual limitation of motions, radiographic criteria and staging of Ficat and Arlet. Radionuclide Scintigraphy (99 mTc Di-phosphonate ) can be done especially for diagnosis in the early stages of osteonecrosis, CT to detect the early details of bone changes, MRI to record very early marrow necrosis not detectable by CT and tests for haemodynamic functions (intramedullary pressure measurements and venography) for vascular stasis.
Osteoporosis is a condition, which advances with age, resulting in fragile, weak bones due to a decrease in bone mass. Externally osteoporotic bone is shaped like normal bone, however it’s internal appearance differs. Internally the bone becomes porous due to a loss in essential minerals, including phosphate and calcium. The minerals are loss more quickly than they can be replaced and in turn cause the bones to become less dense and weak. The bones become prone to fracture, due to their weakness. Therefore the awareness of the disease tends to occur after a fracture has been sustained. The bones most commonly affected are the ribs, wrist, pelvis and the vertebrae.
Osteogenesis imperfecta, also known as “brittle bones disease,” is a rare genetic disorder that affects the body’s production of type I collagen, which is the major protein of the body’s connective tissue. Generally, people affected with OI either have too little of type I collagen, or the quality of it is poor. Collagen defects account for about 85%.1 However, proteins in the bones may be affected in some of the more uncommon forms of OI. Because of this defect, people with OI have fragile bones, which break easily without an apparent cause.
Osteoporosis is a serious disease that leads to a faster than normal loss of the bone density, which puts the bone at a higher risk for fractures. In order to understand the causes of Osteoporosis, it is important to understand how bones are formed. Bone is a living tissue that is made mainly of collagen, calcium phosphate, and calcium carbonate. The mixture of collagen and calcium gives the bone strength and flexibility. The body deposits new bones and removes old ones; moreover, there are two types of bone cells that control the reproduction of bones. Cells called osteoclasts breakdown bone tissues thus, damaging the bone. Once the damaged bone is removed, cells called osteoblasts, use minerals including calcium and phosphate from the blood stream to make new healthy bone tissues. In order for osteoblasts and osteoclasts to work properly, hormones such us thyroid, estrogen, testosterone, and growth hormones are
Hoffmeister, Ellen. "Gene Therapy and Pharmaceuticals Offer Hope for Many Patients With Brittle Bones." Bone and Joint 11.5 (2005): 49-51. eBook.
Fibrodysplasia Ossification Progressiva, or more commonly known as “Stone Man’s Syndrome” because it turns the person into a “Statue”. It is a disorder in which the “soft connective tissue progressively turns to bone.” It is a very rare, and painful disorder. It affects about one person out of 2 million, it is so rare that it can sometimes even be misdiagnosed for other diseases and disorders. Some disorders that FOP is mistaken for would be Juvenile Fibromatosis, Lymphedema, or soft tissue sarcomas. Since it is commonly misdiagnosed, it is also mistreated, and can lead to even more harm for the patient. Because flare-ups can occur with “Muscle or connective tissue trauma, Intramuscular vaccinations, dental work, bumps, bruises or even falls.” The cause of this disease is believed to be “linked to a mutation in activin receptor IA/activin-like kinase 2 (ACVR1/ALK2) a bone morphogenic protein (BMP) type I receptor.
Emerging research and potential treatments in achondroplasia and other skeletal dysplasias. (n.d.). Retrieved March 17, 2014, from http://www.lpaonline.org/research-and-treatments
However some of the basic bone functions include storing of crucial nutrients, minerals and lipids, producing red blood cells for the body, protect the organs such as heart, ribs and the brain, aide in movement and also to act as a buffer for pH. With the differences in all of the bones there are four things that remain the same in each bone, their cells. Bones are made up of four different cells; osteoblasts, osteoclasts, osteocytes and bone lining cells. Osteoblasts produce and secrete matrix proteins and then transport the minerals into the matrix. Osteoclasts are responsible for the breaking down of tissue. The osteoblasts and osteoclasts are both responsible for remodeling and rebuilding of bones as we grow and age. The production of osteoclasts for resorption is initiated by the hormone, the parathyroid hormone. Osteocytes are the mature versions of osteoblasts because they are trapped in the bone matrix they produced. The osteocytes that are trapped continue making bone to help with strength and the health of the bone matrix. The bone lining cells are found in the inactive bone surfaces which are typically found in