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ScienceWeek
MEDICAL BIOLOGY: ON OSTEOPETROSIS
The following points are made by J. Tolar et al (New Engl. J. Med. 2004 351:2839):
1) Bone is a dynamic tissue in which osteoblasts synthesize bone matrix while osteoclasts resorb bone. Therefore, bone density is dependent on the relative function of these two types of cells. Osteoclasts are multinucleated cells of hematopoietic lineage that are critical for bone remodeling; osteoblasts, in contrast, are of mesenchymal origin.[1] Osteoblasts synthesize bone matrix and in so doing lay down a microenvironment that supports osteoclast growth, maturation, and function. They also secrete macrophage colony-stimulating factor (M-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1, and interleukin-6,[2] all of which influence the activities of osteoclasts. Direct interactions between osteoblasts or marrow stromal cells and osteoclast precursors are essential for the differentiation of osteoclasts.[3,4]
2) Osteopetrosis is a heterogeneous group of heritable conditions in which there is a defect in bone resorption by osteoclasts. A century ago, Heinrich Albers-Schöenberg (1865-1921) described the radiographic findings in a patient with increased bone density.[5] Since then, various types of osteopetrosis have been described. The disease is associated with an increased skeletal mass due to abnormally dense bone. Generalized osteosclerosis is apparent radiographically, often with a "bone within a bone" appearance; transverse radiolucent bands may be observed, and it may be difficult to discern the marrow cavity. The decrease in osteoclast activity also affects the shape and structure of bone by altering its capacity to remodel during growth. In severely affected patients, the medullary cavity is filled with endochondral new bone, with little space remaining for hematopoietic cells. This abnormality contributes to the brittleness of bone in osteopetrosis. The abnormal skeletal radiographs and microscopical appearance of bone can be reversed by hematopoietic stem-cell transplantation.
3) Before the changes in genes that affect the function of osteoclasts were identified, osteopetrosis could be categorized only on the basis of the clinical aspects of the three primary types: infantile or "malignant" osteopetrosis, inherited in an autosomal recessive inheritance pattern; "intermediate" autosomal recessive osteopetrosis; and autosomal dominant osteopetrosis. The incidence of autosomal recessive osteopetrosis is approximately 1 in 300,000 births but is almost 10 times as high in Costa Rica. In severe forms of osteopetrosis, the insufficient bone marrow cavity cannot support adequate hematopoiesis. The result is extramedullary hematopoiesis, which causes hepatosplenomegaly. Children who are severely affected can have cranial-nerve dysfunction, and visual deficits are often evident at birth or within the first several months of life. Thrombocytopenia, anemia, and infectious complications commonly cause death within the first decade of life. In less severe forms of osteopetrosis, patients have a normal life expectancy, but the brittle bone frequently fractures, particularly in autosomal dominant osteopetrosis.
4) The origin of osteoclasts from hematopoietic precursors was first suggested by landmark studies in which osteopetrosis in mice was corrected by parabiotic union with normal animals. Subsequently, the transplantation of splenocytes from unaffected littermates was shown to cure the bony manifestations of the disease; moreover, osteopetrosis developed in unaffected animals after transplantation of splenocytes from osteopetrotic animals. These experiments in mice prompted treatment of an infant who had severe osteopetrosis with allogeneic bone marrow transplantation, which corrected the bony and hematologic manifestations in the child.
References (abridged):
1. Wlodarski KH. Properties and origin of osteoblasts. Clin Orthop 1990;252:276-293
2. Taichman RS, Emerson SG. The role of osteoblasts in the hematopoietic microenvironment. Stem Cells 1998;16:7-15
3. Takahashi N, Akatsu T, Udagawa N, et al. Osteoblastic cells are involved in osteoclast formation. Endocrinology 1988;123:2600-2602
4. Udagawa N, Takahashi N, Akatsu T, et al. The bone marrow-derived stromal cell lines MC3T3-G2/PA6 and ST2 support osteoclast-like cell differentiation in cocultures with mouse spleen cells. Endocrinology 1989;125:1805-1813
5. Albers-Schönberg HE. Röntgenbilder einer seltenen Knockenerkrankung. Munch Med Wochenschr 1904;51:365-368
New Engl. J. Med. http://www.nejm.org
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Related Material:
ON TISSUE-ENGINEERED BONE REPLACEMENT
Notes by ScienceWeek
In general, "tissue engineering" is the implantation of living cells with synthetic scaffolding to guide tissue development, the result the generation of new tissue. Although this is not a new technology in clinical medicine, at least in the experimental sense, there have been important advances during the past 20 years, and the field of tissue engineering now has its own research centers, organizations, meetings, and journals. For obvious reasons, there is intense commercial interest in the potential clinical applications of this field.
One area of promise is the use of tissue engineering in bone reconstruction. Bone ordinarily heals itself if fractured, but if a section of bone is lost through disease or accident, that section will not be regenerated in an adult human. A major attempt at clinical bone reconstruction has involved "grafting". A "bone autograft" (also called "autologous bone graft") is a transfer of a bone section from one place to another in the same individual, the process avoiding tissue rejection. In contrast, a "bone allograft" is a bone graft transplanted between genetically non-identical individuals of the same species. (A "xenograft" is a graft between different species.)
During the past several decades, autografts and allografts have been used extensively in clinical medicine to replace bone in human patients. Several natural or synthetic bone substitutes have also been used, either alone or in conjunction with demineralized bone or autologous bone. Also used have been polypeptides or demineralized bone powder to stimulate the differentiation of embryonic connective tissue into bone. Another technique involves the implantation of living cells in conjunction with inert materials. In this type of tissue engineering, living cells are implanted after the cells are seeded into some type of scaffolding or template, the scaffolding guiding tissue regeneration.
In general, the term "connective tissue" refers to tissue which protects and supports the body and its organs, binds organs together, stores energy reserves as fat, and provides immunity. Connective tissue is the most abundant and widely distributed tissue in the mammalian body, with forms ranging from the fluid of blood to the solid substance of bone (osseous tissue).
Like other connective tissue, bone contains an abundant matrix surrounding widely separated cells, the matrix approximately 25 percent water, 25 percent protein, and 50 percent mineral salts. There are 4 types of cells in mammalian bone tissue:
1) Osteoprogenitor cells (stem cells): undifferentiated cells capable of developing into other cell types.
2) Osteoblasts: the cells that form bone, secreting collagen and other organic components needed in bone construction.
3) Osteocytes: mature bone cells derived from osteoblasts, and which are the principal cells of bone tissue. Osteocytes maintain the ongoing cellular activities of bone tissue, such as the exchange of nutrients and wastes with the blood.
4) Osteoclasts: cells on the surface of bone that function in bone resorption (destruction of matrix), which is important in the development, growth, maintenance and repair of bone.
The term "periosteum" refers to the membrane that surrounds the surface of bone not covered by cartilage at a joint. The periosteum consists of two layers, an outer fibrous layer composed of connective tissue containing blood vessels and nerves that pass into the bone, and an inner layer containing blood vessels, elastic fibers, and the all important osteogenic cells that give rise to various types of bone cells.
Unlike other connective tissues, the matrix of bone contains abundant mineral salts, primarily a crystallized form of tri-calcium phosphate called hydroxyapatite.
The following points are made by C.A. Vacanti et al (New Engl. J. Med. 2001 344:1511):
1) The authors report the use of tissue-engineering to replace the end bone (distal phalanx) of the thumb in a 36-year-old patient who had had this part of his left thumb torn away in a machine accident. The team reports that the procedure resulted in the functional restoration of a stable and biomechanically sound thumb of normal length, the procedure without the pain and complications that are usually associated with harvesting a bone graft.
2) The researchers point out that tissue-engineered bone has many advantages over autologous bone or bone obtained from cadavers, and advantages over synthetic materials that are not seeded with cells. Bone autografts that are not anchored to adjacent bone are usually resorbed, and are thus not an effective long-term treatment. In addition, harvesting of bone autografts often results in pathology at the donor site. Like bone autografts, bone from cadavers is also usually resorbed, and such bone grafts carry the added risk of disease transmission from the donor tissue. Synthetic materials used without cells are also subject to degradation, and such materials can produce foreign-body reactions or inflammation detrimental to the implant and surrounding tissues.
3) The tissue-engineered bone produced in this case involved the use of coral (porous hydroxyapatite) as a scaffold. When coral alone is not in direct contact with bone, no bone forms within it. But when coral is seeded with bone marrow cells, or with cells derived from the periosteum, and placed in subcutaneous tissue that is not adjacent to native bone, new bone forms. In this particular patient, the coral scaffold was seeded with cells from the periosteum. The research team concluded: "The current case suggests that the use of tissue-engineered bone may be an effective approach to the treatment of bone loss due to trauma or disease."
New Engl. J. Med. http://www.nejm.org
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Related Material:
CELL BIOLOGY: ON THE FORMATION OF BONE
The following points are made by P. Ducy et al (Science 2000 289:1501):
1) A mineralized tissue that confers multiple mechanical and metabolic functions to the skeleton, bone contains two distinct cell types, bone-forming cells (osteoblasts), and bone-resorbing cells (osteoclasts), and these two cell types participate in a variety of important physiological processes during development and postnatal life.
2) The term "bone formation" is sometimes used to describe osteoblast specialization (osteoblast differentiation) during embryonic development (skeletogenesis). Bone formation is implicated directly or indirectly in longitudinal bone growth, bone mineralization, and the ongoing resorption and replacement of bone (bone remodeling) -- all functions that are not easily studied _in vitro_. Our understanding of the molecular control of osteoblast function has been greatly enhanced by the emergence of gene-deletion technology.
3) The functions of osteoblasts and osteoclasts are intimately linked. During skeletal development and throughout life, cells from the osteoblast lineage synthesize and secrete molecules that in turn initiate and control osteoclast differentiation. This is a direct and crucial interaction that has been well established _in vivo_. Once osteoblasts and osteoclasts are fully differentiated, there is a less direct relationship. Bone is constantly destroyed or resorbed by the osteoclasts and then replaced by the osteoblasts in a physiological process called "bone remodeling". Various experiments involving alterations in genes (genetic models) indicate that the osteoblasts do not influence the activity of the osteoclasts in any overt way _in vivo_. Nevertheless, bone remodeling is tightly regulated by *local and endocrine factors. The endocrine regulation of bone resorption has been well known for many years, but it is only recently that bone formation has been shown to be under endocrine control.
4) The study of the biology of osteoblasts illustrates how mammalian genetics has profoundly modified our understanding of cell differentiation and physiological processes. Genetics-based studies over the past 5 years have revealed how osteoblast differentiation is controlled via *growth factors and *transcription factors. Similarly, the recent identification, using mutant mouse models, of a central nervous system component in the regulation of bone formation has expanded our understanding of the control of bone remodeling. This regulatory loop, which involves the hormone leptin, may help to explain the protective effect of obesity on bone mass in humans. In addition, it provides a novel physiological concept that may shed light on the etiology of *osteoporosis and help to identify new therapeutic targets.
Science http://www.sciencemag.org
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Notes by ScienceWeek:
local and endocrine factors: In general, "endocrine" mechanisms are mechanisms involving secretions of substances (hormones) into the systemic circulation, i.e., a global (vs. local) chemical communication pathway.
growth factors: In general, in this context, a "growth factor" is any specific substance that must be present in a culture medium for multiplication of the cultured cells to occur.
transcription factors: "Transcription" is the process by which the genetic information in DNA is converted into RNA, and transcription factors are a class of DNA-binding proteins that regulate RNA transcription.
osteoporosis: A generalized progressive diminution of bone density (bone mass per unit volume) that causes skeletal weakness. The ratio of mineral to organic elements is unchanged. The major clinical manifestations of osteoporosis are bone fractures resulting from a reduction below the fracture threshold of the amount of bone available for mechanical support.
ScienceWeek http://scienceweek.com
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