Blood Calcium Level - Calcium Hydroxyapatite

Calcium is used for several processes within the body, including muscle contraction, metabolism, nerve impulses, and the formation of blood clots. There are specialized bone cells that are involved with maintaining normal blood calcium levels so these processes can be carried out. Bone cells are called osteocytes. Within a bone, inorganic salts (salts that do not contain carbon) and collagen surround the osteocytes. This is called the intercellular matrix. Cylindrical sections of matrix and osteocytes are called osteons, and each osteon has a central canal containing blood vessels and nerves. The salts of the matrix are mostly hydroxyapatite, which is a form of calcium phosphate. Osteoclasts are a type of bone cell that breaks down hydroxyapatite to release calcium into the blood. Osteoblasts build intercellular matrix from the excess calcium in the blood. These bone cells are stimulated by different hormones. When blood calcium levels are too low to sustain the physiological processes of the body, parathyroid hormone is released and osteoclasts are stimulated to break down the hydroxyapatite. When blood calcium levels are high, the thyroid releases calcitonin. Calcitonin stimulates osteoblasts to store calcium in the bone matrix. While the bones are necessary for movement and structural support, they greatly affect other physiological processes as well. Red marrow is the site of blood cell formation. Blood calcium levels dictate the calcium content of bones. Specialized osteocytes release calcium into the blood and build bone matrix from excess blood calcium.

Formation
The formation of bone during the fetal stage of development occurs by two processes: Intramembranous ossification and endochondral ossification. [edit]Intramembranous

ossification

Intramembranous ossification mainly occurs during formation of the flat bones of the skull but also the mandible, maxilla, and clavicles; the bone is formed from connective tissue such as mesenchyme tissue rather than from cartilage. The steps in intramembranous ossification are: 1. Development of ossification center 2. Calcification 3. Formation of trabeculae 4. Development of periosteum

[edit]Endochondral

ossification

Endochondral ossification

Endochondral ossification, on the other hand, occurs in long bones and most of the rest of the bones in the body; it involves an initial hyaline cartilage that continues to grow. The steps in endochondral ossification are: 1. Development of cartilage model 2. Growth of cartilage model 3. Development of the primary ossification center 4. Development of the secondary ossification center 5. Formation of articular cartilage and epiphyseal plate Endochondral ossification begins with points in the cartilage called "primary ossification centers." They mostly appear during fetal development, though a few short bones begin their primary ossification after birth. They are responsible for the formation of the diaphyses of long bones, short bones and certain parts of irregular bones. Secondary ossification occurs after birth, and forms the epiphyses of long bones and the extremities of irregular and flat bones. The diaphysis and both epiphyses of a long bone are separated by a growing zone of cartilage (the epiphyseal plate). When the child reaches skeletal maturity (18 to 25 years of age), all of the cartilage is replaced by bone, fusing the diaphysis and both epiphyses together (epiphyseal closure). [edit]Bone

marrow

Bone marrow can be found in almost any bone that holds cancellous tissue. In newborns, all such bones are filled exclusively with red marrow, but as the child ages it is mostly replaced by yellow, orfatty marrow. In adults, red marrow is mostly found in the marrow bones of the femur, the ribs, the vertebrae and pelvic bones.

Remodeling
Remodeling or bone turnover is the process of resorption followed by replacement of bone with little change in shape and occurs throughout a person's life. Osteoblasts and osteoclasts, coupled together via paracrine cell signalling, are referred to as bone remodeling units. [edit]Purpose The purpose of remodeling is to regulate calcium homeostasis, repair micro-damaged bones (from everyday stress) but also to shape and sculpture the skeleton during growth. [edit]Calcium balance The process of bone resorption by the osteoclasts releases stored calcium into the systemic circulation and is an important process in regulating calcium balance. As bone formation actively fixescirculating calcium in its mineral form, removing it from the bloodstream, resorption actively unfixes it thereby increasing circulating calcium levels. These processes occur in tandem at site-specific locations. [edit]Repair Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of maximum stress (Wolff's law). It has been hypothesized that this is a result of bone'spiezoelectric properties, which cause bone to generate small electrical potentials under stress.[12] [edit]Paracrine

cell signalling

The action of osteoblasts and osteoclasts are controlled by a number of chemical factors that either promote or inhibit the activity of the bone remodeling cells, controlling the rate at which bone is made, destroyed, or changed in shape. The cells also use paracrine signalling to control the activity of each other. [edit]Osteoblast

stimulation

Osteoblasts can be stimulated to increase bone mass through increased secretion of osteoid and by inhibiting the ability of osteoclasts to break down osseous tissue. Bone building through increased secretion of osteoid is stimulated by the secretion of growth hormone by the pituitary, thyroid hormone and the sex hormones (estrogens and androgens). These hormones also promote increased secretion of osteoprotegerin.[13] Osteoblasts can also be induced to secrete a number of cytokines that promote reabsorbtion of bone by stimulating osteoclast activity and differentiation from progenitor cells. Vitamin D, parathyroid hormone and

stimulation from osteocytes induce osteoblasts to increase secretion of RANKligand and interleukin 6, which cytokines then stimulate increased reabsorbtion of bone by osteoclasts. These same compounds also increase secretion of macrophage colony-stimulating factor by osteoblasts, which promotes the differentiation of progenitor cells into osteoclasts, and decrease secretion of osteoprotegerin. [edit]Osteoclast

inhibition

The rate at which osteoclasts resorb bone is inhibited by calcitonin and osteoprotegerin. Calcitonin is produced by parafollicular cells in the thyroid gland, and can bind to receptors on osteoclasts to directly inhibit osteoclast activity. Osteoprotegerin is secreted by osteoblasts and is able to bind RANK-L, inhibiting osteoclast stimulation.[13] [edit]Disorders See also: List of skeletal disorders There are many disorders of the skeleton. One of the more prominent is osteoporosis. [edit]Osteoporosis Main article: Osteoporosis Osteoporosis is a disease of bone, leading to an increased risk of fracture. In osteoporosis, the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral density 2.5 standard deviations below peak bone mass (20-year-old sex-matched healthy person average) as measured by DEXA; the term "established osteoporosis" includes the presence of a fragility fracture.[14] Osteoporosis is most common in women after the menopause, when it is called postmenopausal osteoporosis, but may develop in men and premenopausal women in the presence of particular hormonal disorders and other chronic diseases or as a result of smoking and medications, specifically glucocorticoids, when the disease is called steroid- or glucocorticoid-induced osteoporosis (SIOP or GIOP). Osteoporosis can be prevented with lifestyle advice and medication, and preventing falls in people with known or suspected osteoporosis is an established way to prevent fractures. Osteoporosis can be treated with bisphosphonates and various other medical treatments.

Hematopoiesis is the process by which immature precursor cells develop into

mature blood cells. The currently accepted theory on how this process works is called the monophyletic theory which simply means that a single type of stem cell gives rise to all the mature blood cells in the body. This stem cell is called the pluripotential (pluripotent) stem cell.

SITES OF HEMATOPOIESIS
Age of animal Embryo
rd th

Site of hematopoiesis yolk sac then liver marrow cavity - esp. granulocytes and platelets marrow cavity - erythrocytes mostly bone marrow; spleen and liver when needed number of active sites in bone marrow decreases but retain ability for hematopoiesis bone marrow of skull, ribs, sternum, vertebral column, pelvis, proximal ends of femurs

3 to 7 month spleen 4th and 5th months 7th month Birth Birth to maturity Adult

STRUCTURE & FUNCTION OF BONE MARROW

Bone marrow has a vascular compartment and an extravascular compartment. The vascular compartment is supplied by a nutrient artery which branches into central longitudinal arteries which send out radial branches that eventually open into sinuses. These sinuses converge into a central vein that carries the blood out of the bone marrow into the general circulation. Hematopoiesis takes place in the extravascular compartment. The extravascular compartment consists of a stroma of reticular connective tissue and a parenchyma of developing blood cells, plasma cell, macrophages and fat cells. The high activity of the bone marrow is demonstrated by its daily output of mature blood cells: 2.5 billion erythrocytes, 2.5 billion platelets, 50-100 billion granulocytes. The numbers of lymphocytes and monocytes is also very large. Bone marrow is the site for other important activities in addition to hematopoiesis. These include the removal of aged and defective erythrocytes and the differentiation of B lymphocytes. It is also the site of numerous plasma cells.

THE PROCESS OF HEMATOPOIESIS

The monophyletic theory of hematopoiesis states that pluripotent stem cells multiply to produce more pluripotent stem cells, thus ensuring the steady and lasting supply of stem cells. Some of the pluripotent stem cells differentiate into precursor cells that are at least partially committed to become one type of mature blood cell.

Pluripotent stem cells multiply slowly into one of five possible unipotential stem cells which then multiply rapidly into the precursor of the specific mature blood cell for which they are destined.

Although the pluripotent stem cells and the unipotential stem cells cannot be distinguished from one another histologically, the precursor cells can be distinguished with a trained and practiced eye.

General Features: Understanding the general process of hematopoiesis will be

extremely helpful in distinguishing and identifying the different cells in a bone marrow smear or in an intact bone marrow preparation. Basically an immature, precursor cell goes from a cell that is making lots of protein to a cell that is making much less protein.

Since structure is (always) related to function, the structure of the precursor cell changes as it goes from making more protein to making less protein. Thus, a cell that is making a lot of protein will have a nucleus containing dispursed or active chromatin, i.e., that is being transcribed actively. When this cell is making less protein, the chromatin is condensed or clumped because it is not being transcribed. Likewise, a cell that is making a lot of protein will have many and large nucleoli, the site of ribosomal RNA synthesis and assembly; as protein secretion decreases there are smaller and fewer nucleoli. Cells with high protein synthetic activity have more ribosomes in their cytoplasm and consequently the cytoplasm stains more basophilic (hematoxylin staining of the RNA in ribosomes). Cells with lower protein synthetic activity have fewer ribosomes, thus less basophilic staining with hematoxylin leaving the cytoplasm appearing more acidophilic due to the eosin staining of cytoplasmic proteins. Cells with high protein synthetic activity the Golgi apparatus is highly developed, occupies much of the cytoplasm thus pushing the nucleus off to one side (acentric nucleus). Cells with low protein synthetic activity have a smaller Golgi and the nucleus tends to be more centrally located. The chart below summarized these features.

ERYTHROPOIESIS
As the cells are maturing In the erythrocytic series, the cells are usually getting smaller, the nucleus is becoming smaller and more condensed and is eventually lost, and the cytoplasm is becoming more pink rather than blue. The cells in the developing erythrocyte series are as follows:

Micrographs from bone marrow smear from adult dog. (Lab slide 38A)

Unipotent stem cell: not shown, cannot be distinguished from other unipotent stem cells histologically

Proerythroblast: nucleus still rather large, taking up most of the cell; nucleus not condensed; cytoplasm still very blue or basophilic Basophilic erythroblast: not shown; very difficult to distinguish from the proerythroblast

Polychromatophilic erythroblast: nucleus is more condensed than that of the proerythroblast; cytoplasm less blue, more grayish Orthochromatophilic erythroblast: nucleus more condensed, smaller than that of previous cells and looks pyknotic by comparison; cytoplasm beginning to take on a more pinkish cast

Reticulocyte: no nucleus; cytoplasm still stains somewhat bluish due to presence of remnants of polyribosomes Erythrocyte: mature erythrocyte has no nucleus (in mammals); cytoplasm stains very pink due to lack of ribosomes and presence of high amounts of protein, i.e., hemoglobin

GRANULOCYTE DEVELOPMENT

Unipotent stem cell: not shown, cannot be distinguished from other unipotent stem cells histologically

Micrographs from bone marrow smear from adult dog. (Lab slide 38A)

Myeloblast: large cell with bluestaining cytoplasm; large nucleus; often as in this example, a clear area near the nucleus can be seen this is where the rather large Golgi is located

Metamyelocyte: cell is about the size of a mature granulocyte; nucleus with slight indentation; granules present that stain appropriately for the series, i.e., pink for eosinophilic, blue for basophilic, neutral for neutrophilic

Promyelocyte: example not shown; still a rather large cell with azurophilic (not specifically stained) granules

Myelocyte: example not shown; overall cell still rather large; nucleus still round without indentation; granules staining appropriately for the series, i.e., pink for eosinophilic, blue for basophilic, neutral for neutrophilic

Band cell: cell is about the size of a mature granulocyte; nucleus with definite indentation - looks like a horseshoe; prominent granules that stain appropriately for the series Mature (segmented) granulocyte: cell is mature and looks like normal, mature granulocytes in the blood with lobed nucleus and prominent granules that stain appropriately for the series

MONOCYTES
Not responsible for knowing the sequence of development of monocytes.

LYMPHOCYTES
Since mature lymphocytes look essentially like their precursor cells and pluripotent stem cells, intermediate forms cannot be identified histologically.

PLATELETS
Platelets, also called thrombocytes, play an important role in hemostasis by. plugging holes in blood vessels to prevent bleeding promoting formation of clots to further prevent bleeding

helping to repair damaged blood vessels

Platelet granules contain the secretory material that platelets produce to help repair damaged blood vessels, growth factor and many other proteins. Some of these are:

platelet factor 4 - regulates vascular permeability, calcium mobilization from bone, chemotaxis of monocytes and Micrograph of smear of monk neutrophils stain (Lab slide L). beta thromboglobulin - function unknown; used to monitor activation of platelets in some diseases Platelets appear as round, oval or bic coagulation factors - fibrinogen, factor V, factor VIII diameter of about 1.5 to 3.5 m. The see in blood smears because of their s fibronectin, thrombospondin, platelet-derived growth are often clumped together. Despite t factor - all may be involved in repair of damaged blood all of the normal organelles and are r vessels difficult to resolve with the light micr serotonin (taken up from plasma and stored in granules) seen with the electron microscope. lysosomal enzymes such as hydrolases

Platelets are formed in the bone marrow from megakaryocytes

(30-100 m diameter), very large cells with a polyploid, multilobed nucleus. Platelets are released from fragmenting megakaryocytes in at least two ways:

extension of pseudopodia through the wall of the sinuses; pseudopodia contain "strings" of platelets that are pinched off and released into the circulation passage of mature megakaryocyte into circulation and fragmenation in the pulmonary vascular bed

Micrograph of fetal bone of Arrows indicates two of the the megakary