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1

What are the histologic features of bone?

2

What are the different types of bone and how are they each characterized?

3

What are the cellular origins of bone and cartilage cells?

4

List the factors the affect osteoblasts and osteoclasts?

5

which transcription factors turn mscs into bone?

Transcription factor RUNX2 and bone morphogenetic protein (BMP) direct mesenchymal cells to the osteoblast lineage.

6

what do osteoblasts make?

Alkaline phosphatase

Osteocalcin (stimulated by 1,25dihydroxyvitamin D [1,25(OH)2D3])

Type I collagen

Bone sialoprotein

Receptor activator of nuclear factor (NF)-κβ ligand (RANKL)

Osteoprotegerin—binds RANKL to limit its activity

7

how does wnt affect bone?

Wnts are proteins that promote osteoblast survival and proliferation.

Deficient Wnt causes osteopenia; excessive Wnt expression causes high bone mass.

Wnts can be sequestered by other secreted molecules such as sclerostin (Scl) and Dickkopf-related protein 1 (Dkk-1).

8

how does sclerostin interact with bone formation?

Sclerostin secreted by osteocytes helps negative feedback on osteoblasts’ bone deposition

9

bone cells and their interaction

10

cartoon of how osteoclasts are regulated

11

key testable facts about osteoclasts

Multinucleated irregular giant cells

Derived from hematopoietic cells in macrophage lineage

Monocyte progenitors form giant cells by fusion

Function

Bone resorption

Bone formation and resorption are linked

Stimulated primarily by RANKL binding to RANK receptor on cell surface

Osteoblasts (and tumor cells) express RANKL (Fig. 1.4):

Binds to receptors on osteoclasts

Stimulates differentiation into mature osteoclasts

Inhibited by osteoprotegerin (OPG) binding to RANKL

Occurs both normally and in certain conditions, including multiple myeloma and metastatic bone disease

Denosumab is a monoclonal antibody that targets and inhibits RANKL binding to the RANK receptor

12

what are the resorptive methods of osteoclasts?

Osteoclasts possess a ruffled (brush) border and surrounding clear zone

Border consists of plasma membrane enfoldings that increase surface area

Bind to bone surfaces through cell attachment (anchoring) proteins

Integrin (αvβ3 or vitronectin receptor)

Bone resorption occurs in depressions: Howship lacunae.

Effectively seal the space below the osteoclast

Synthesize tartrate-resistant acid phosphate

Produce hydrogen ions through carbonic anhydrase

Lower pH

Increase solubility of hydroxyapatite crystals

Organic matrix then removed by proteolytic digestion through activity of the lysosomal enzyme cathepsin K

13

List the Organic and Inorganic components of bone:

Organic components: 40% of dry weight of bone

Collagen (90% of organic components)

Primarily type I (mnemonic: bone contains the word one)

Type I collagen provides tensile strength of bone

Hole zones (gaps) exist within the collagen fibril between the ends of molecules.

Pores exist between the sides of parallel molecules.

Mineral deposition (calcification) occurs within the hole zones and pores.

Cross-linking decreases collagen solubility and increases its tensile strength.

Proteoglycans

Matrix proteins (noncollagenous)

Osteocalcin: most abundant noncollagenous protein in bone

Inhibited by PTH and stimulated by 1,25(OH)2D3

Can be measured in serum or urine as a marker of bone turnover

Inorganic (mineral) components: 60% of dry weight of bone

Calcium hydroxyapatite [Ca10(PO4)6(OH)2]: provides compressive strength

Calcium phosphate (brushite)

14

what is the most abundant noncollagenous protein in bone? 

Osteocalcin

15

what provides the compressive strength of boen

Calcium hydroxyappetite

 

different from subchondroplasty (calcium phosphate)

16

Describe the different types of bone formation:

17

what is enchondral bone formation?

Examples:

Embryonic formation of long bones

Longitudinal growth (physis)

Fracture callus

Bone formed with demineralized bone matrix

Undifferentiated cells secrete cartilaginous matrix and differentiate into chondrocytes.

Matrix mineralizes and is invaded by vascular buds that bring osteoprogenitor cells.

Osteoclasts resorb calcified cartilage; osteoblasts form bone.

Bone replaces the cartilage model; cartilage is not converted to bone.

Embryonic formation of long bones

18

How is endochondral ossification stimulated?

Differentiation stimulated in part by binding of Wnt protein to the lipoprotein receptor–related protein 5 (LRP5) or LRP6 receptor

19

Review of the growth plate

20

Review the Cartoon of MSCs in bone

21

Cartoon of the enchondral ossification of bone

22

Review the clinically relevant zones of the growth plate:

Reserve zone: cells store lipids, glycogen, and proteoglycan aggregates; decreased oxygen tension occurs in this zone.

Lysosomal storage diseases (e.g., Gaucher disease) can affect this zone.

Proliferative zone: growth is longitudinal, with stacking of chondrocytes (the top cell is the dividing “mother” cell), cellular proliferation, and matrix production; increases in oxygen tension and proteoglycans inhibit calcification.

Achondroplasia causes defects in this zone (see Fig. 1.11).

Growth hormone exerts its effect in the proliferative zone.

Hypertrophic zone:

Divided into three zones: maturation, degeneration, and provisional calcification

Normal matrix mineralization occurs in the lower hypertrophic zone: chondrocytes increase five times in size, accumulate calcium in their mitochondria, die, and release calcium from matrix vesicles.

Chondrocyte maturation is regulated by systemic hormones and local growth factors (PTH-related peptide inhibits chondrocyte maturation; Indian hedgehog protein is produced by chondrocytes and regulates the expression of PTH-related peptide).

Osteoblasts migrate from sinusoidal vessels and use cartilage as a scaffolding for bone formation.

Low oxygen tension and decreased proteoglycan aggregates aid in this process.

This zone widens in rickets (see Fig. 1.11), with little or no provisional calcification.

Mucopolysaccharide diseases (see Fig. 1.11) affect this zone, leading to chondrocyte degeneration.

 

Physeal fractures probably traverse several zones, depending on the type of loading (Fig. 1.12).

23

describe the grooves of ranvier and perichondral ring of lacroix

Groove of Ranvier: supplies chondrocytes to the periphery for lateral growth (width)

Perichondrial ring of La Croix: dense fibrous tissue, primary membrane anchoring the periphery of the physis

24

what is intramembraneous ossification?

Occurs without a cartilage model

Undifferentiated mesenchymal cells aggregate into layers (or membranes), differentiate into osteoblasts, and deposit an organic matrix that mineralizes.

Examples:

Embryonic flat bone formation

Bone formation during distraction osteogenesis

Blastema bone (in young children with amputations)

25

What is oppositional ossification?

Osteoblasts align on the existing bone surface and lay down new bone.

Examples:

Periosteal bone enlargement (width)

Bone formation phase of bone remodeling

26

Describe bone remodeling

27

what is the Heuter Volkmann Law?

remodeling occurs in small packets of cells known as basic multicellular units (BMUs).

Such remodeling is modulated by hormones and cytokines.

Compressive forces inhibit growth; tension stimulates it.

Suggests that mechanical factors influence longitudinal growth, bone remodeling, and fracture repair

May play a role in scoliosis and Blount disease

28

Describe Wolff's law:

remodeling occurs in response to mechanical stress.

Increasing mechanical stress increases bone gain.

Removing external mechanical stress increases bone loss, which is reversible (to varying degrees) on remobilization.

Piezoelectric remodeling occurs in response to electric charge.

The compression side of bone is electronegative, stimulating osteoblasts (formation).

The tension side of bone is electropositive, stimulating osteoclasts (resorption).

29

what are the biomechanical and biological factors affecting bone repair?

30

Describe the stages of fracture repair:

Inflammation

Fracture hematoma provides hematopoietic cells capable of secreting growth factors.

Subsequently, fibroblasts, mesenchymal cells, and osteoprogenitor cells form granulation tissue around the fracture ends.

Osteoblasts (from surrounding osteogenic precursor cells) and fibroblasts proliferate.

Repair

Primary callus response within 2 weeks

For bone ends not in continuity, bridging (soft) callus occurs.

Soft callus is later replaced through enchondral ossification by woven bone (hard callus).

Medullary callus supplements the bridging callus, forming more slowly and later.

Fracture healing varies with treatment method (Table 1.6).

 

In an unstable fracture, type II collagen is expressed early, followed by type I collagen.

Amount of callus is inversely proportional to extent of immobilization.

Progenitor cell differentiation

High strain promotes development of fibrous tissue.

Low strain and high oxygen tension promote development of woven bone.

Intermediate strain and low oxygen tension promote development of cartilage.

Remodeling

Remodeling begins in middle of repair phase and continues long after clinical healing (up to 7 years).

Allows bone to assume its normal configuration and shape according to stress exposure (Wolff’s law)

Throughout, woven bone is replaced with lamellar bone.

Fracture healing is complete when the marrow space is repopulated.