Physiology of bone self study week 2

Question 1

What are 4 fxns that bones provide?

Answer 1

1. structural integrity (support)
2. movement of limbs
3. storage of calcium and phosphate

hematopoiesis

Question 2

What are the 2 main compositions of bone? What cells are responsible for producing them?

Answer 2

1. type 1 collagen (organic matrix) (30%)
2. calcium phosphate (hydroxyapatite-inorganic matrix) (68%)

collectively referred to as matrix of bone. comprises 98% of bone

cells within bone are responsible for their production: osteocytes and osteoblasts (2%)

Question 3

What 4 processes occur in bone? (give names and definitions)

Answer 3

1. growth: begins in fetus and ceases at end of pubery
2. modeling: altering structure of bone in response to mechanical loads placed on it
3. remodeling: repair of micro-damage
4. repair: occurs when trauma damages bone

modeling and remodelling occur continuously (even after growth phase)

Question 4

True or false: Bone is a very metabolically active tissue.

Answer 4

True. Although it is composed of only 2% of cells, these cells are highly metabolically active. Bone receives more blood flow than resting skeletal muscle and kidney

Question 5

Where to osteoblasts originate? Where are they located? What is their fxn?

Answer 5

1. mesenchymal stem cells
2. surface of bone (periosteum and endosteum)
3. formation of bone

Question 6

Where to osteocytes originate? Where are they located? What is their fxn?

Answer 6

1. matured osteoblasts
2. located within bone (in mineralized portions)
3. mechanotransduction: sensing mechanical strain and sending signals to osteoblasts to take action. also fxn in clacium and phosphate transport

Question 7

What are the origins of periosteal and endosteal cells? Where are they located? What is their fxn?

Answer 7

1. originate from osteoblasts
2. periosteum and endosteum
3. regulate movement of calcium and phosphate into and out of bone

Question 8

What are the origins of osteoclasts? Where are they located? What is their fxn?

Answer 8

1. hematopoietic stem cells (specialized macrophages)
2. surfaces of bone: periosteum and endoteum.
3. resorption of bone. use H+ to break down mineralized portions and proteases to degrade organic portions

Question 9

Mesenchymal stem cells (osteoprogenitor cells) develop into preosteoblasts which then develop into osteoblasts. What 2 hormones stimulate the production of osteoblasts from preosteoblasts?

Answer 9

Vitamin D and PTH. both fxn to increase blood Ca2+. since players in Ca2+ homeostasis, it makes sense that they would lead to development of more active cells that are responsible for Ca2+ homeostasis in bone

Question 10

Describe the precursors that lead to formation of osteoclasts (starts with hematopoietic stem cells)

Answer 10

1. hematopoietic stem cells
2. osteoclast precursors
3. mononuclear osteoclasts
4. multinuclear osteoclasts

Question 11

What 2 factors can osteoblasts release to stimulate osteoclast formation and where in the pathway do they act?

Answer 11

osteoblasts release M-CSF (macrophage colony stimulating factor) and stimulates formation of osteoclast precursors from hematopoietic stem cells. M-CSF acts in concert with RANKL (Receptor Activator of NF-_KB Ligand) which is the ligand for RANK. RANK is a receptor on osteoclasts precursor membranes and induces osteoclastgenesis

see pg 12 of course notes (did not place here bc contains info that is in future cards)

Question 12

What hormone is the primary endocrine regulator of bone remodeling in adults? How does it stimulate osteoblasts and osteoclasts?

Answer 12

1. PTH (parathyroid hormone)
2. stimulates preosteoblasts to turn into osteoblasts. only osteoblasts express receptors for PTH. Therefore, PTH directly stimulates osteoblast activity and indirectly stimulates osteoclast activity through release of M-CSF and RANKL from osteoblasts. M-CSF and RANKL stimulate osteoclast formation

Question 13

How can PTH stimulate bone formation and resorption? What hormone/vitamin is needed for PTH to have its effects and what happens without it?

Answer 13

1. intermittent administration of low doses of PTH promotes osteoblast survivla and bone anabolic fxns, incrases bone density, and reduces risk of fx. sustained, elevated levels of PTH shift balance to a relative increase in osteoclast activity-increase in bone turnover and reduction in bone density. so, lower basal levels cause bone fomration and higher levels (such as levels seen when plasma Ca2+ drops, PTH causes bone resorption and mobilization of Ca2+ from bone.
2. vitamin D. without it, normal levels of Ca2+ are less effective at suppressing PTH secretion and increased bone resorption results

Question 14

What do osteoblasts produce to form bone?

Answer 14

produce collagen (predominantly type 1). collagen type 1 forms fibrils and fibers. osteoblasts then mineralize collagen with calcium phosphate salt (hydroxyapatite). crystals lodge in the spaces in and around collagen molecules and are oriented along the length of fibers. mixture of fibers and mineral gives bone its great mechanical strength

Question 15

What factor allows for mineralization of collagen type 1 (secreted into matrix by osteoblasts) through formation of P_i (inorganic phospate) from PP_i (pyrophospate)? Why is P_i produced? What portion of the osteoblast is it found?

Answer 15

TNAP hydrolyzes PP_i to form P_i. P_i is neded for formation of hydroxyapatite. it is located on the cell surface of osteoblasts

Question 16

Osteoblasts mineralize bone matrix by promoting ______ crystal formation and growth in the interior membrane-limited matrix vesicles (MV’s). and by precipitating the crystals onto the collagenout ECM.

Answer 16

hydroxyapatite. Do this through TNAP

please see pg 17 of self study to understand this

Question 17

True or false: Although calcium phospate ions are present in most body fluids (including bone) in high enough concentrations to lead to precipitation of calcium salts, this does not occur because of the presence of agents that inhibit this reaction.

Answer 17

True. please see pg 17 of notes to understand this concept

Question 18

What is the most important factor osteoblasts produce to promote deposition of salts in the oranic matrix of bone?

Answer 18

TNAP

Question 19

What role does PP_i play in formation of hydroxyapatite? NPP1 (ectoplasmic PC-1/nucleotide pyrophosphatase/phosphodiesterase-1)? ANK (ankylosis protein?

Answer 19

1. PP_i inhibits matrix mineralization. it is formed by NPP-1 located in ECM from ATP and ADP. ANK is a transporter on osteoblasts that passes PP_i into the ECM-inhibits hydroxyapatite formation

please see pg 17 of notes

Question 20

What role does osteopontin (OPN) play in mineralization? What is thought to control its expression and under what conditions does its expression increase?

Answer 20

1. OPN is a protein that when its high number of serine residues are phosphorylated generate a great deal of negative charge. negative charge allows it to strongly bind calcium atoms available at surface of hydroxyapatite and acts to inhibit further mineralization
2. expression is not well understood but is under control of vitamin D and expression is increase with hypocalcemia and hypophosphatemia (makes sense because cannot produce hydroxyapatite if do not have enough of the minerals that compose it)

see pg 17 of notes

Question 21

What is bone sialo protein (BSP) and what role does it play in mineralization of bone?

Answer 21

is thought to serve as a part of the collagen matrix and sesrve as a nidus (place where something is formed or deposited) for crystalization of hydroxyapatite

Question 22

What is hypophosphatasia? What enzyme is mutated in this disease? How severe is this disease? How is it diagnosed biochemically?

Answer 22

due to deficiency in TNAP enzyme that results in less bone mineralization. Severity is variable and is modulated by nauture of TNAP mutation. range from complete absence of bone mineralization and stillbirth to spontaneous fractures and loss of decidual teeth in adult life. diagnosed by low levels of serum TNAP and accumulation of phosphocompounds such as PP_i

Question 23

What is the fxn of osteoclasts? How do they attach do bone? What is the ruffled border? What does it secrete?

Answer 23

1. responsible for bone resorption by destroying the matrix and freeing up calcium phosphate salts
2. integrin receptors. form a tight seal to precent leakage of acidic contents to surrounding tissues
3. invaginated plasma membrane structure interfaced with bone. acts as a huge lysozyme by secreting HCl onto the surface. also secretes proteases

Question 24

What is the source of acid that osteoclasts secrete? What pumps are used to secrete it?

Answer 24

1. pumps protons via protons produced from activity of carbonic anhydrase: CO_{2 +}H_2O = H₂CO_{3<span>=</span>} H⁺ + HCO₃^-
2. pumps HCl using an ATP dependent proton pump and a chloride channel (similar mechanism used to produce stomach acid). HCO₃^- is pumped out of cell via Chloride carbonate exchanger

Question 25

What protease is released from osteoclasts? What is done with the products?

Answer 25

1. capthesin K
2. products are taken into the cell and released in bone canaliculi that connect to the vascular compartment

Question 26

What are the 2 fxns of osteocytes? Where are they located within bone? How do they communicate with other cells?

Answer 26

1. sensing mechanical load and contributing to Ca2+ and PO4 homeostasis by makig possible the movement of these electrolytes into and out of bone
2. within mineralized portions of bone. are matured osteoblasts
3. send cytoplasmic processes into canaliculi. form a functional syncetium via gap junctions btwn one syncytial process and the next cell body they are in contact with. osteocyte syncytial processes also extend to osteblasts on surface of bone (how they stimulate their activity). strain due to mechanical load on bone causes movement of bone fluid that is present in canaliculi that surrounds osteocytes. fluid movement is transduced into an electrical signal that alters fxn of osteocytes and to osteoblasts to which they are functionally connected. repeated strain on boan causes bone remodeling.

fxn in calcium homestasis through osteocytic osteolysis: when stimulated directly by PTH (during low Ca2+ concentrations) stimulated osteocytes free up Ca2+ from their local micro-environment and active pumps move calcium into plasma compartment. only limited amnt of calcium is freed but does serve to maintain a normal Ca2+ concentration in the face of disturbances that would reduce it

Question 27

True or false: Long bones grow in both length and diameter.

Answer 27

True.

Question 28

True or false: Growth in length in long bones takes place as the cartilage ends of the bone (epipiphyses) continues growing and secondary centers of ossification appear.

Answer 28

True.

Question 29

In endochondral ossification of long bones, proliferation of chondrocytes occurs at the (epiphyseal/diaphyseal) side and replacement by bone occurs at the (epiphyseal/diaphyseal) side.

Answer 29

1. epiphyseal (in growth plate)
2. diaphyseal

Question 30

What 3 types of hormones is growth of bones stimulated by?

Answer 30

1. growth hormone (GH)
2. IGF-1 (insulin like growth factor)
3. sex hormones

Question 31

What is bone modeling?

Answer 31

changes that occur in long bones of growing individuals to math the structure of the bone to mechanical loads placed on that bone. involved coordinated osteoclastic and osteoblastic activity. involves alteration of existing bone. continues in adults in absence of growth in the length of bones

Question 32

What is bone remodeling? How does it work? How does it change with age and why? How is osteoprotegerin involved?

Answer 32

serves 2 essential functions: contributes to calcium regulation by moving calcium into or out of bone and repairs inevitable micro-damage that occurs. is a continually active process even during bone growth. occurs in an orderly cycle in which old bone is resorbed by osteoclasts (forming a resorption pit) and osteblasts fill the pit and form new bone

remodeling involves tight coupling btwn osteoclasts and osteoblasts. btwn ages of 20 and 30, there is nearly an exact balance of these 2 processes. after age of 30 or so, there is a slow loss of bone mass at the rate of osteoclastic activity that exceeds rate of osteoblastic activity. is in part driven by gradual decrease in circulating estrogen in women and testosterone in men

osteoprotegrin is a signal osteoblasts can send that acts as a soluble decoy for RANKL (inhibits its fxn) so that proosteoclastic signal from osteoblasts is terminated. happens after about 2 weeks of bone resorption

Question 33

What disease can mutations in RANK/RANKL and OPG cause?

Answer 33

RANK/RANKL: stimulate osteoclastic activity. mustatins can cause osteopetrosis

OPG (osteoprotegerin): inhibits osteoclastic activty through inhibition of RANKL. mutation can cause osteoporosis

Question 34

What effects do PTH, Vitamin D, calcitonin, estrogen, testosterone, IGF, thyroid hormone, and glucocorticoids (cortisol) have on osteoclastic and osteoblastic activity?

Answer 34

Question 35

Discuss the process of bone repair. be sure to discuss inflammation, hematomas, fibrin, periosteum changes, and soft and hard calluses.

Answer 35

inlammatory response due to fracture is produced by destruction of blood vessels. a hematoma develops with a network of fibrin fibers that serve as anchors for precursor cells that migrate into area of fracture. new capillaries grow into the hematoma and fibroblasts migrate into the region. the periosteum proliferates and connective tissue is formed resulting in a soft callus that anchors the two ends of fractured bone. osteoprogenitor cells give rise to osteoblasts that begin to lay down new mineralized bone resulting in hard callus. hard callus consists of woven bone (immature bone) which undergoes remodeling into lamellar bone.