16 - Bone as a Tissue and Organ

Question 1

What are two types of bone? How do they differ and how are they the same? What percentage of bone does each make up?

Answer 1

Cortical (compact) bone makes up 80-85% and trabecular (cancellous) bone makes up 15-20%.

They contain the exact same cellular and matrix elements, but serve different functions.

Question 2

What is the structure of cortical/compact bone on histology? How does this structure confer function?

Answer 2

It’s organized as osteons (aka haversion systems): cylindrical structures in which concentric layers of bone matrix form lamellae around a central canal.

The lamellar organization of osteons contributes to the bone’s ability to resist fracture.

Question 3

What is the primary function of cortical bone?

Answer 3

Primarily structural, providing protection for organs and levels used for movement.

Question 4

What is the appearance/structure of trabecular bone on histology?

Answer 4

Trabecular bone is normally organized in a lamellar fashion, but the individual trabeculae are too small to contain osteons.

Question 5

What is the primary function of trabecular bone? How does its structure help confer function?

Answer 5

It’s primarily metabolic: it accounds for most of the bone surface area and most of the remodelign activity.

The large SA is necessary to allow for mineral homeostasis.

Question 6

What are the two developmental pathways of bone?

Answer 6

Intramembranous ossification and endochondral ossification

Question 7

Describe the change in skeletal muscle mass through puberty and young adulthood in young males vs females? Why does this occur?

Answer 7

Mass increases for both through puberty and young adulthood, but does so to a greater extent in males than females.

• Puberty is later in males - leading to a larger body size
• Hormones in males promote greater modeling than in females - greater diameter in bone

Question 8

How does skeletal mass change in the third decade of life for men vs women? What is the significance of this?

Answer 8

Net mass declines, but does so in a way that results in a greater decrease in mass in females than males.

This contributes to a higher susceptibility of females to fracture.

Question 9

How is intramembranous bone formed? What are examples of bones that are intramembranous in origin?

Answer 9

By formation of osteoblasts from mesenchymal stem cells within what will become the periosteum.

The bone is formed de novo.

Exp. bones of the skull and the ribs.

Question 10

________ bone is also formed in the bone collar region of a healing fracture and at the periosteal surface of long bones as they model. What does this allow them to achieve?

Answer 10

Intramembranous bone.

This allows them to achieve a greater diameter.

Question 11

What is endochondral bone? How do they grow? What is an examples of endochondral bone?

Answer 11

Endochonrdal bones replace previously formed cartilage models.

They grow in length by proliferation of chondrocytes within the growth plate; linear growth ceases when the growth plates fuse.

Exp. long bones of the limbs

Question 12

What is the growth plate?

Answer 12

Highly organized tissue in which chondrocytes are arrayed in colums, with different opsitions of the column occupied by cells as distinct points of maturation.

Question 13

What are the zones of the growth plate and how does each function?

Answer 13

1. Chondrocytes in the proliferation zone divide to replenish the growth plate.
2. The chondrocytes then hypertorphy, undergo apoptosis, and are mineralized.
3. Blood vessels invade the zone of calcified cartilage, which is resorbed by chondroclasts and the space is filled by osteoblasts and boen matrix.

Question 14

Linear growth of long bones depends on what? When do growth plates close in humans?

Answer 14

The relative speed at which cells in the hypertrophic zone undergo apoptosis and those in the proliferative zone divide.

Growth plates close in late adolescence in response to estrogen signaling; the epiphysis at different sites fuse at different ages.

Question 15

Which type of bone is remodeling much more actively?

Answer 15

Trabecular, which makes sense because of its more prominent role in maintaining mineral homeostasis.

Question 16

What two principles are essential in understanding the bone remodeling cycle (ie about the speed of this proces)?

Answer 16

1. Resorption is relatively rapid - requiring ~2 weeks
2. Bone formation is slow, requiring 4-6 months for full mineralization to occur

Question 17

Remodeling of trabecular bone provides a mechanism by which extracellular fluid can do what?

Answer 17

Buffer its calcium and phosphate content.

PTH and 1,25 di-PH vitamin D are potent activators of osteoclast activity, and bone resorption involves dissolution of the bone mineral, thus providing free Ca and PO4 that can enter the EC fluids and blood.

(this is because PTH signals that Ca is LOW and the bone should be resorbed)

Question 18

How much Ca is exchanged by trabecular bone each day? What is this essential for?

Answer 18

Approx. twice the amount that is absorbed from food or lost in the urine each day.

Active exchange of minerals between the bone and circulation is essential for moment to moment mineral homeostasis.

Question 19

Bones can grow not only length-wise, but in radial size and shape. What is this aspect of growth called? What is it mediated by? Give an example.

Answer 19

Called modeling and is partly mediated by physiological responses to mechanical loading.

Exp: elite racquet sport athletes have more radial bone growth in their dominant arm than their non-dominant arm.

Question 20

At the level of the whole bone, __________ is the primary stimulus to modeling. What seems to be important at the level of the cell?

Answer 20

Whole bone: strain (fractional change in length)

Cell: shear stress, requiring both anchoring of osteocytes by focal adhesion complexes and fluid flow sensed by each cell’s primary cilium.

Question 21

What allows new bone growth to be directed to the sites experiencing the greatest strain?

Answer 21

The connections among osteocytes via their processes allows integration of the response acress cells.

Question 22

What signaling pathway is a critical regulator of bone modeling in response to mechanical loading? Describe this process and what inhibits it.

Answer 22

Wnt signaling pathway:

• canonical WNT signaling via B-catenin promotes osteoblast proliferation and matrix synthesis
• mature osteocytes, when unlaoded, secrete sclerostin (SOST) an inhibitor of WNT signaling

Question 23

What effect does mechanical loading have on sclerostin (SOST)?

Answer 23

Loading inhibits SOST synthesis by osteocytes, resulting in de-repression of the WNT pathway (ie WNT pathway is on and can promote osteoblast proliferation and matrix synthesis).

Question 24

Define strain. What does pure compression cause? What about pure stretching?

Answer 24

The fractional change in length of a structure as a result of a force being applied to it

• pure compression causes negative strain
• pure stretching causes positive strain

.

Question 25

Mechanical loading results in a mixture of _______ and _______.

Answer 25

Compression and tension.

Question 26

How are bones able to resist damage by tension or compression?

Answer 26

Compressive strength comes from the mineral phase (~2/3 of the bone ECM by mass)

Tensile strength comes from the protein and water (~1/3 of the bone ECM by mass)

Question 27

What is the primary component of bone’s ECM? Describe the structure.

Answer 27

Type 1 collagen:

• Large triple helical protein that self-assembles into fibrils with an offset of ~1/4 the molecule length, leading to a stiped appearance on EM.

Question 28

What does the pattern of type I collagen assembly result in?

Answer 28

• Empty spaces that are thought to function as nucleation sites for the mineral phase.
• Adjacent molecules are covalently cross-linked, which mature to aromatic pyridolines and deoxypyridinolines.
• The mature cross-links have a high bond energy and are thus hard to break.

Question 29

What does the helical structure of individal collagen molecules allow?

Answer 29

Allows them to be stretched along the axis like springs, providing another mechanism by which collagen imparts tensile strength to the bone matrix.

Question 30

Ca and PO4 are the most abundant ions in bone mineral, but what other compounds are present in significant amounts? What best describes the mineral in bone?

Answer 30

Mg, Na, OH, CO3, SO4, and Cl.

Mineral in bone = apatite.

Question 31

What does apatite result from? What function does this serve?

Answer 31

Substitution of hydroxyapatite with other ions.

This decreases the regular structure of the mineral lattice and makes energy needed to solubilize ions. This occurs at the cost os stiffness but is important in promoting mineral homeostasis.

Question 32

The mineral phase of bone is intercalated into what?

Answer 32

The collagen fibril structure, this appears to be done passively.

Question 33

What are potent inhibitors of mineralization? What modulates mineralizatoin?

Answer 33

Sulfate and pyrophosphate are potent inhibitors.

Proteins in the SIBLING (small integrin-binding ligand, N-linked glycoprotein) family are modulators of mineralization and account for most of the non-collagenous protein secreted by osteoblasts.

Question 34

What property of bones provides toughness and the ability to resist the propagation of a fracture?

Answer 34

The lamellar structure; the interfaces between lamellae and between the osteons (called cement lines) can absorb and dissipate force while preventing a crack from passing from one lamella to its neighbor.

Question 35

Bone toughness is anisotrophic, what does this mean?

Answer 35

Transverse cracks are less able to propogate than are longitudinal cracks.

Question 36

What is osteogenesis imperfecta caused by?

Answer 36

Mutations in the genes encoding type 1 collagen or critical enzymes in the assembly and processing of type 1 collagen.

Results in deficient production or improper assembly of ECM

• susceptibility to fracture and other tissue abnormalities in places containing large amounts of type 1 collagen.

Question 37

Osteogenesis imperfecta can be thought of as a pure ______ disease.

Answer 37

Osteoblast.

Question 38

What is osteomalacia? What can cause it?

Answer 38

Disease that results from inadequate mineralization of the bone matrix and can be a consequence of several conditions:

• Malabsorptive disorders
• VitD deficiency/resistance
• Phosphate wasting disorders
• Low Ca2+ diet

Question 39

What does osteomalacia result in? What happens when it occurs in growing individuals?

Answer 39

Weak, undermineralized bones.

In growing pts: bone modeling is abnormal and the long bones assume a bowed shape - called rickets.

Question 40

What can rickets be thought of as?

Answer 40

A disorder in which the bone cells function normally, but lack the appropriate mineral substrates leads to abnormal bone function.

Question 41

What are sclerosteosis and Van Buchem’s disease?

Answer 41

Disorders in which the skeletal mass is abnormally high due to mutations of the protein sclerostin (SOST).

This disturbs the mechanosensory system, resulting in bones perceiving that they are being loaded even when they are not.

Question 42

Overgrowth of bone in sclerosteosis can lead to what symtpoms?

Answer 42

Nerve entrapment, causing facial palsy and deafness.

Some mutations can also cause syndactyly (fingers together).

Question 43

Sclerosteosis and Van Buchem’s disease can be thought of as _____ diseases.

Answer 43

Osteocyte

Question 44

What is osteopetrosis?

Answer 44

Group of diseases in which osteoclast function or maturation is impaired and thus remodeling is deficient.

It’s a disorder of impaired resorption - bone is fragile because it doesn’t have the normal lamellar architecture.

Question 45

Why are severe cases of osteopetrosis lethal?

Answer 45

The marrow space is not formed and hematopoiesis is severely impaired.

Instead of being lamellar, the bone is woven (premature).

Question 46

Osteopetrosis can be thought of as a pure _____ disease.

Answer 46

Osteoclast disease

Question 47

What is the result of osteopetrosis?

Answer 47

Inability to remodel bone, which results in bones that while dense and massive are nevertheless weak because they are unable to assume the lamellar structure that remodeling produces.