Skeletal Healing/Osteoimmunology (Lecture 6) Flashcards by J L

Fracture healing process
• Intramembranous bone from the ____
– joins the fractured ends together

• Endochondral bone formation
– forms a ____ which stabilizes fracture healing
– movement of bone during fracture healing would otherwise interfere with union of fractured bone

periosteum

callus

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Endochondral Bone Formation in Fracture Repair

Initial Response

____ formation/Fibrin clot
Activation of BMSC/Recognition Response

first event that occurs is inflammation; a formation of a ____

inflammation is important in fracture healing because it activates the ____; the SC come from the ____; they migrate from the bone and take care of both the intramem and endochondral healing

hematoma
hematoma
SC
periosteum

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Fracture callus

a stabilizing callus that prevents ____ during the healing process

movement

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Stages of Fracture Repair

Initial Injury:
____
____ recruitment

Periosteal Response:
Vascular In-growth
____ bone formation

Primary Bone Formation:
Cartilage Formation Osteoclast removal cartilage
____
____ bone formed

Secondary Bone Formation:
Osteoclast ____
Coupled Osteoblast Establishment of ____ Remodeling to original form

inflammation
sc

intramembranous

vascularization
endochondral

remodeling
marrow

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Fracture healing occurs in stages

____
Inflammation
Recruitment of ____
Cartilage formation
Cartilage resorption/vascularization
Bone formation
Bone remodeling and removal to reduce excess bone

____ for endochondral
____ for intramembranous

fracture
SC
OB
chondrocytes

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Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation

this is a similar mechanism to what you would see in a ____ (proliferating, hypertrophic, etc.)

growth plate

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The Initial Hematoma Releases GF to Stimlate the Repair Process

first step: hematoma/inflammation; kicks off the repair by releasing GF from ____ (a rich resource of GF)

PDGF-BB (specific to ____), FGF-2, VEGF, IGF-1, TGF-beta

____ and ____ also release GF; MSC release factors important for ____ that is important for inducing the epithelium

platelets
platelets
WBC
MSC
vascularization

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Fracture Repair and SC

MSC form fat, bone and muscle tissue; in healing fracture, the MSC migrate from the ____: away from bone: form ____, towards bone: ____

____ OF CELL determines what it will become

periosteum
chondrocytes
osteoblasts

spatial location

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Endochondral Bone Formation in Fracture Repair

Proliferative response Mesenchymal Stem Cells
____ Cells

Tissue Formation Chondrocytes – cartilage
Osteoblasts – ____ bone

Endochondral ossification
Cartilage calcification
Invasion of blood vessels
Removal of cartilage and replacement by bone

formation of a hard ____

the initial cartilage calcifies > hard callus, which is ____; gets invaded by BV, contains OPC > stimulated into osteoclasts > removal of cartilage > ____ are released and new cells come in which form the calcified bone

endothelial
intramembranous

callus
functionally stable
signals

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Endochondral Bone Formation

The first event that occurs is the hematoma and inflammation. This causes platelets to degranulate, and inflammatory cells to migrate
and release ____. This leads to the stimulate of stem cells. They can lead to ____ and ____ bone
formation to repair the bone.

The area of endo bone formation stimulates stem cells to produces chondrocytes that produces cartilage.

The OC and vascularization and stem cells migrate in again which leads to bone formation. This is an anabolic formation of tissue, this
is followed by catabolic prices. The overall reaction is ____ because there is more OC activity than bone formation.

growth factors
endochondral
intramembranous

catabolic

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Intramembranous bone formation and remodeling

For intra bone formation, stem cells will
differentiate into ____. This will lead to
____ formation = bone formation.
This new bone gets remodeled
(____).

osteoblasts
anabolic
catabolic

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Chondrogenic and Osteogenic TF in Fractures

why do you get SC forming chondrocytes and in another forming OB

the reason is: you have TF that are induced by local signals > when cells migrate from periosteum away from the bone > signals they receive induce these TF > differentiation of chondrocytes > migrate toward bone: ____ and ____ > formation of OB [occurs within the early event of the MSC]; or ____ and ____ for formation of chondrocytes

These transcription factors bind to the ____ region

runx2
osterix
sox9
sox5

promoter

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Angiogenesis and Fracture Healing

Angiogenesis plays an important role in bone formation by providing ____ that are needed for formation of osteoid and mineralization of bone.

BV bring cell types with them: the OPC travel through BV; it also brings nutrients, and they are surrounded by a ____ (which are ____) > important when you have a ____ from cartilage to bone

nutrients
pericytes
MSC
transition

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Bone healing in extraction sites

Trabecular bone formation occurs in ____ stages of bone healing. Two ways to form woven bone after tooth extraction:

1) Trabecular bone from existing bone surfaces (blue arrows)
- Osteoclast-____
- ____ coupling

2) ____ woven bone with osteoblasts derived from mesenchymal stem cells that migrate into extraction socket (red arrows)
- Osteoclast-____

occurs ____; if you drill a hole in the alveolar bone it won’t heal as quickly as the removal of a tooth

the ____ is loaded with cells that can form bone (mostly MSC-like cells)

early
dependent
osteoclast-osteoblast

de novo
independent

spontaneously
PDL

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Osteoimmunology

Interaction between the ____ and bone

immune response

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If you look at someones mouth, you can see inflammation but you dont know if it is from the
bone. You can see that the gingiva is the same. But you have no idea what the bone levels
are. You need to ____ to measure the bone height or take an ____. You cannot diagnose just
from ____ at it.

probe
x-ray
looking

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• Gingivitis

Inflammation of the gingiva that is ____
Does ____ cause periodontal bone loss

• Periodontitis
- Inflammation causes periodontal ____; ____

• Periodontal diseases
- Includes both ____ and ____

reversible
not
bone loss
irreversible
gingivitis
periodontitis

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Pathogenesis of Periodontal Disease

Stimulated by ____.
Bacteria stimulate inflammation:
• ____ immune response (e.g. PMNs, macrophages)
• ____ immune response (e.g. lymphocytes)
Immune cells (leukocytes) produce ____ that
initiate and amplify the level of inflammation.
Cytokines stimulate ____ formation.

bacteria
innate
adaptive
cytokines
osteoclast

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Periodontitis

once barrier is comprimised, the bacteria can cross the epithelium > when bacteria see the cells, ____ are released and leukocytes enter

as the bacteria migrate deeper, it gets closer to bone > ____ is very importnat; when its close to bone > formation of ____ > bone resorption > ____ blocks the repair process of bone

____ blocks the regeneration of bone which should be always followed by resorption

chemokines
spatial inflammation
osteoclast
inflammation
inflammation

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Phagocytes:
____ and
____ that kill bacteria and secrete
____ which affect other cells to increase inflammation

Dendritic cells: Capture microbes and
____ them to lymphocytes.

Phagocytes are the ____ line of dense against bacteria. Nuetrophils and macrophages produce cytokines that stimulate other inflammatory

cells. The inflammatory cells work in ____, they dont work alone. you need the ____ immune response for the phagocytes to be
effective. The phagocytes dont recognize the bacterial that well, so when the Abs bind to them, the phagocytes recognize them ____.

____ is also necessary. Phagocytes work better when stimulated by cytokines. Macrophages work better when stimulated by ____. This interaction is important is needed in an effective immune response when bacteria keep invading into the gingival
tissue.

macrophages
neutrophils
present

first
networks
adaptive
better

T cell activation
gamma interferon

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Adaptive Immunity
• Presentation of antigen by antigen presenting cell
• Antigen presented to ____
• Results in lymphocyte activation

The primary antigen presenting cell is the ____. Other cells are also capable of
presenting antigen including ____ and ____. They present antigen in the lymph node
which leads to the activation of lymphocytes. These two arms of the immune response talk
to each other and make each other more effective.

lymphocytes

dendritic cell
monocytes
B cell

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Lymphocytes:

B cells – produce ____ and ____
T cells – kill ____, regulate other ____ and produce ____

antibody
cytokines
cells
lymphocytes
cytokines

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Bacteria Induce Cytokine Production in Macrophages

Bacteria stimulate macrophages to produce cytokines (____ and ____). This has a big effect on ____ so
macrophages and neutrophils also act on each other.

IL-1 (inflammation)
TNF
neutrophils

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Antigen Presentation Activates Lymphocytes

Antigen presentation activates ____. The ____ present themselves to the T cells, the T cells produce cytokines that lead
to macrophage activation through ____. It leads to inflammation through ____ that leads to regulation of T and B lymphocytes
that leads to the production of other factors.

lymphocytes
dendritic cells
gamma interferon
TNF

Oral Pathogen ``` The important source of RANKL is the T and B lymphocyte that is activated by the ____ immune response which is why the immune response leads to bone ____ through the production of RANKL. ``` ``` The ____ (TNF-alpha, IL-1beta, IL-6) produced by innate response also stimulate the production of ____. RANKL can be produced by ____ presentation and can be induced by ____ produced by the innate immune response. This forms the ____ and OC degeneracies and loss of periodontal bone. ```

adaptive resorption ``` inflammatory mediators RANKL antigen inflammatory mediators OC precursors ```

Inflammatory Cytokines Needed for anti-bacterial defenses by ____ the innate and adaptive immune response that kill microbes Also stimulate ____ processes Inflammatory cytokines have beneficial and destructive capabilities If inflammatory cytokines are inhibited how does this affect periodontitis? inhibiting inflam cytokines > increase the risk of ____, and the risk of the infection ____ > big scare is the infection expanding beyond the ____

upregulating destructive infection spreading fascial plane

Cytokines May Stimulate or Inhibit Osteoclast Formation The cytokines are produced and once they're activated, there is a second system that comes and shuts it down. The immune system gets activated but it is also a system that can shut down. Think of the immune system as ____ and ____. Ex: when his mother in law stays for a couple of days, it is pleasant and nice. And then she leaves and it is also pleasant and nice. If his mother in law doesn't leave, it can create a chronic low level problem. That's what happens in periodontal disease. Think of bacteria has your mother in law. The cytokines that stimulate inflammation are in red. The factor that inhibit inflammation or cause it to leave are in blue. If you have an episode of inflammation, it stays for a short period of time, a repair process can kick in and repair the tissue damage. If the inflammation stays and interferes with the repair process, the damage becomes ____. You need to think about they yin and yang of pro and anti inflammation. Inflammation is just as important The bold and large font factors are particularly important for both activating and causing resolution of the inflammation OPG is osteoprotegerin that binds to ____ and induces the formation of OC. It acts as a blocking agent. ____ inhibits the effect of RANKL meaning it shuts down inflammation and leads to resolution.

acute chronic permanent RANKL IL-10

RANKL RANKL is a key cytokine for stimulating ____ that resorb bone RANK is the receptor for RANKL that is found on ____ and ____ RANKL is blocked by binding of ____ The ____ of RANKL to OPG is important in determining whether osteoclast formation is stimulated

``` osteoclasts osteoclast precursors osteoclasts osteoprotegerin (OPG) ratio ```

RANKL - RANKL is a cytokine primarily produced by ____ and ____ under physiologic conditions during bone remodeling. - RANKL is also produced by ____ (e.g. lymphocytes) in inflammatory conditions (pathologic bone resorption) in addition to bone lining cells and osteocytes. ____ cells are also an important source of RANKL; prevent these cells from secreting RANKL you can prevent periodontal disease

bone lining cells osteocytes leukocytes PDL

RANKL vs. OPG You have more OPG than RANKL. Most of OPG binds to RANKL and prevents RANKL from stimulating to OC activity If RANKL is stimulating, you have excess RANKL, and not enough OPG, leading to a lot of OC. So, inflammation ____ RANKL and ____ OPG. The change from ____ to ____ leads to bone resorption.

increases decreases homeostatic inflammatory

Host Response • Plays a critical role in protecting the host from bacteria (protective). • Plays an essential role in periodontal disease and endodontic infections (destructive). • Is both protective and destructive. • The ____, ____ and ____ of the host response will determine whether it ultimately protects or causes resorption of periodontal bone. when a pt comes in with a periodontal abscess, you need to ask the pt when their inflammation started. This is very important! If it started within a ____, most of the bone will regenerate if it is treated. If it is left untreated, there is really negative impact on the repair process. IF the acute inflammation is short, it is ____ to repair. IF the acute or chronic inflammation is long, it is much ____ to repair the damage. DURATION is important.

composition spatial location duration week easy difficult

Inflammatory Infiltrate and Alveolar Bone Loss - The closer the cells of the inflammatory infiltrate are to the bone the more ____ appear and the more bone is degraded the closer the inflam cells are to the bone; the more OC that form > if location is near ____, no permanent damage is experienced again, cannot tell by looking at a patient whether they have gingivitis or resorption

osteoclasts | epithelium

Progression of Inflammatory Cells Toward Bone in Experimental Periodontitis As periodontal disease progresses, the inflammation near the ____ becomes increasingly prominent.

bone

Gingivitis- you have bacteria can penetrate the epithelial barrier and stimulate the gingival. If it is close to the epithelial, and not close to bone, it won't have ____. If the bacteria or their products come in closer proximity to the bone, that leads to recruitment of inflammatory cells close to the bone and the production of inflammation in ____ near the bone and formation of OC. THIS IS NOT SOMETHING YOU CAN TELL ____.

bone resorption cytokines visually

Onset and Resolution of Periodontal Inflammation What is the time course of inflammation after experimentally induced periodontitis? What is depth of an inflammatory infiltrate during and after experimentally induced periodontitis?

NEXT Q

Resolution of Periodontal Inflammation In Experimental Periodontitis If you take a pt and you treat them, the inflammation in the periodontitis will ____ substantially. It happens ____. If the inflammation is new, it can allow the repair to occur if treated. So if you have a periodontal abscess, you can remove the bacteria, which is the ideological stimulus. You can scale the pt to remove the ideological factor,. Then you can treat with antibiotic if you think the bacteria will spread. The antibiotic will prevent ____ and help with the scaling. This is the inflammation that is close to the bone. When you treat it, the inflammation close to the bone goes ____ quickly.

decrease rapidly reinvasion away

Prostaglandins contribute to periodontal bone loss • Periodontal bacteria stimulate the generation of ____. • Prostaglandin are ____ mediators. ---Prostaglandin is a lipid based material that causes inflammation. It has been shown that prostaglandin is important in stimulating ____ • The enzymes that produce prostaglandins are induced by ____. ---Bacterial infection -> causes production of prostaglandin -> induces inflammation • Prostaglandins enhance ____ formation.

prostaglandins lipid periodontal bone loss bacterial infection osteoclast

Prostaglandins contribute to periodontal bone loss * Inhibiting prostaglandins ____ periodontal bone loss. * Demonstrates that the production of prostaglandins stimulated by bacteria is involved in periodontal breakdown. block prostaglandins, bacteria were present, and you inhibited periodontal bone loss; this proves that ____ is the key factor in stimulating bone loss can place prostaglandins in toothpaste, can cross the ____ without much trouble

reduce inflammation epithelial barrier

Prostaglandins Stimulate Macrophages to Produce Cytokines That Stimulate Osteoclast Formation Prostaglandin stimulates ____ and ____. These cells produce ____, ____, and ____. They also are involved in activating the immune response. The adaptive and innate immune response is triggered by ____ leading to ____ formation.

``` macrophages monocytes RANKL TNF-alpha IL-1 prostaglandin OC ```

RANKL is Produced by T-cells and B-cells to Stimulate Osteoclast Formation In Inflammatory Bone Loss dendritic cells: they are found in the ____ and in ____ surrounding the epithelium; capture antigen in gingiva, bring to lymph nodes > activation of ____ > activation of ____ > activated B/T cells will migrate back into gingiva to produce ____ and ____ to increase OC formation ``` 1. You need the migration of dendritic cells from gingiva to ____ 2. Migration of lymphocytes from lymph nodes to gingiva. 3. The transit allows the lymphocytes to be ____ 4. The activated lymphocytes will fight the bacteria where needed. ```

``` epithelium connective tissue T cells B cells cytokines RANKL ``` lymph node activated

The case for RANKL mediating periodontal bone loss - Inhibition of RANKL reduces ____ in mice and rats.

periodontal bone loss

Inhibition of RANKL with OPG Reduces Osteoclast Numbers in a Rat Ligature Model induce periodontal disease; treat with OPG, block periodontal disease (OPG doesn't block inflammation directly) why can this not be done in humans? - failure of bone remodeling > resulting in ____ (if given systemically) - if given locally > OPG is a protein, difficult to deliver to area and get past the ____ (can make a ____ that has same shape as RANK) OPG doesn't just affect bone, it also affects other ____ > forms a type of compromise that is dangerous

osteonecrosis of jaw epithelial barrier memetic structures

Inhibition of RANKL with OPG Reduces Osteoclast Numbers in a Rat Ligature Model For animals, we can give them ____ (ibuprofen) and it will block periodontal disease. But cannot give it to humans because when you stop taking them, you can a huge ____ that doesn't make it practical. So, if you prescribe a toothpaste with prostaglandin, it would work and reduce inflammation, but once they stop using it, they will lose all of the ____ and lose all of their teeth. There are also systemic side effects

prostaglandin inhibitor rebound bone

In periodontitis the genetic deletion of ____ reduces bone loss. This is most likely due to the fact that without TNF the overall level of ____ is reduced. Less inflammation – reduced stimuli for ____ formation TNF > anti-bacterial defense, ____ production, directly stimulate ____...

``` TNF receptor signalling inflammation osteoclast RANKL osteoclasts ```

Deleting TNF Receptors in a Periodontal Model * Reduces the capacity to deal with ____ – there is a greater bacterial infection with genetic deletion of TNF receptors. * Despite the greater bacterial infection there is less ____. Deleting TNF receptors reduces the neutrophil and PMNs to kill bacteria. When you block TNF, you reduce bone loss. Everytime you modulate inflammation, you get an increase in bacteria. In the long run, there will be a problem. We dont know when the periodontal occurs or not, we only know that the pt previously lost bone. You can assume they are susceptible and you can treat them with scaling and root planing or surgery. You want to reduce the likelihood it will occur again. If you give a drug, you need to give the drug all the time b/c you dont know WHEN the pt has active bone loss or not. This makes drug delivery very difficult. We dont want to give them the drug unless we know they have active bone loss. We dont a have way to determine when pt has active bone loss.

bacteria | bone loss

IL-1 – primarily produced by ____ immune cells (____ and ____)  IL-1 levels in humans are ____ in patients with periodontal disease  Inhibition of IL-1 in a non-human primates ____ periodontal bone loss  Application of IL-1 increases ____ near bone and bone loss in a rat ligature model

``` innate macrophages PMNs elevated reduces inflammation ```

``` Immune Regulation of Bone Resorption in Periodontal and Endodontic Diseases Dendritic cells presentation -> ____ activation -> stimulates ____ -> produce ____ -> B and T cells produce ____ -> ____ cells, ____ cells, and ____ produce RANKL. This all play a role that leads to a stimulated OC and bone loss occurs. ```

``` T cell macrophages RANKL PDL bone lining osteocytes ```

Immune Cells Affect Both Osteoclasts and Osteoblasts ``` There is a balance between bone resorption and bone formation. Peritoneal disease not just bone loss, but you dont repair the bone loss. The interaction between the immune cells stimulating the resorption and blocking the repair process is probably how ____ affects periodontitis. ``` ``` The immune cells are listed here. They produce factors that lead to to the stimulation of OC from a ____. ``` ``` This leads to the formation of OC. This process of resorption causes this stimulation of OB. In periodontal tissue, this resorption process stimulating new bone formation is critical and should occur. However, it doesn't occur. The MSCs should form OB but they are blocked by these ____. ``` ``` The catabolic occurs, but the ____ process doesn't occur. The MSCs to OB differentiation and the OB to produce new bone is being compromised in an inflammatory environment. ```

inflammation hematopoietic SC inflammatory cells anabolic

Cellular Changes in Conversion from Gingivitis to Periodontitis are Linked to Inflammation * Increase in leukocytes (____) * Decrease in Bone Lining and PDL cells (____) When you convert from gingivitis to periodontal, you ____ the number of bone lining cells in the PDL. The inflammation is killing the cells that are able to form ____. The cells that form OB are in the ____ and are ____. When you kill these cells, you will not end up with bone formation inflammation kills the cells you need to form bone. Inflammation leads to ____. When you inject TNF into tumor, the cytokines are capable of inducing ____ -> You have problem in stimulating repair

recruitment apoptosis decrease OB PDL bone lining TNF cell death

Control of bone formation * Proliferation of precursors * Differentiation of precursors to osteoblasts * Stimulation of matrix production ____ limits each of these events (also kills the precursors)

inflammation

Osseous Defects from Uncoupled Bone Formation Once OC form, they stimulate the events which lead to formation of OB. There are 2 ways bone resorption leads to OB formation: 1. There are ____ stored in bone, we you resorb bone, the factors are released and OB form 2. The activity of OC leads to a recruitment of a ____ that produces factors to stimulate OB. In pt with periodontitis. The bone repair is not complete because of the ____. The bacteria that caused the inflammation limits this process.

growth factors monocyte-like cell inflammation

Effect of Inflammation on Osteoblast Numbers * Reducing the effect of inflammation on osteoblasts ____ the number of osteoblasts following periodontal infection. * Increasing inflammation in osteoblasts caused osteoblast ____ in vitro. * Reducing osteoblast cell death significantly increased the amount of ____ following an episode of periodontal bone loss.

increased cell death periodontal bone formation

Inflammation Affects Bone Formation: * Suppresses the production of ____ * Suppresses the production of ____

differentiation factors | growth factors

Investigated How Diabetes Affects Reparative Bone Formation in Periodontal Disease Progression OC precursors are stimulated and produce OC. Then it produces these growth factors. These (BMP-2, BMP-6, FGF-2, TGF-beta) are all produced following ____. They stimulate MSCs to form ____ Inflammation reduces these ____ -> blockage of ____ and matrix production of OB. No adequate bone formation.

bone resorption OB growth factors differentiation

TNF Inhibition Bone Formation Following Induction of Experimental Periodontitis This is in an animal. Periodontal is blocked at this point and there is a small amount of bone formation. If you inhibit inflammation by blocking ____ -> you get more bone formation. So that shows that ____ is blocking the repair process that should occur in periodontal disease.

TNF | inflammation

Effect of Blocking NF-kB in Osteoblast Lineage Cells • Inflammation stimulates activation of the transcription factor ____ • NF-kB regulates expression of other genes -NF-kB is a transcription factor that stimulates a program (increased ____). When its activated, the inflammatory events of that cell increase dramatically. So you can block the ____ of the cell by blocking NF-kB. Once it gets activated, that cell acts like an ____ cell. NF-kB coordinates the inflammation ____ a cell. * NF-kB coordinates the inflammatory response in a cell * If NF-kB is blocked in a cell it prevents the cell from ____ to inflammatory stimuli. * Blocking NF-kB in osteoblasts reduces ____ due to oral infection

``` NF-kB inflammation inflammation inflamed within ``` responding periodontal bone loss

Effect of Blocking NF-kB in Osteoblast Lineage Cells * ____ periodontal bone loss induced by oral infection * Demonstrates that the effect of ____ on osteoblasts is a key component of periodontitis. * Inflammation suppresses the expression of ____ and blocks coupled ____ to create a bone lesion.

Prevents inflammation bone matrix proteins bone formation

Summary Slide (mine) when you lose barrier, bacteria enter > inflammation > leads to recruitment of WBC, inflam cells > these cells can produce ____ > if the WBC are close to the epi > no problem; if the WBC become close to bone > cause bone cells to produce RANKL > now RANKL is close to the bone activating the ____ > after OC are produced, a program of bone formation should occur, but doesn't occur in enough vigor to repair all the bone loss!

RANKL | osteoclast resorption

Summary Slide (tammy's) Periodontal bone loss is simulated by ____ (periodontal pathogen) or their factors (such as ____). When this barrier function is lost, the products can penetrate into the epithelium into the connective tissue and cause inflammation. That inflammation will lead to the recruitment of a number of ____ (including PMNs, macrophages, lymphocytes). White blood cells can produce ____. If these WBCs are close to the epithelium, it doesn't cause much problem. However, if these WBCs become close to bone, they cause bone cells to produce ____. These cells are in or on bone meaning RANKL is very close to bone. If RANKL is close to bone, it is a PROBLEM. RANKL that is far from the ____ will not stimulate OC. Where the RANKL is being ____ is very important. If the lymphocyte is right next to the bone, it produces RANKL, it will cause resorption. If the lymphocyte is next to the epithelium, it won't. RANKL stimulates preOC to form active OC. After the OC are produced, a program of bone formation should occur and that program of bone formation doesn't occur with enough vigor in pt with periodontal disease.

bacteria LPS WBC RANKL RANKL bone produced