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=='''CONNECTIVE  TISSUE'''==
Connective tissue forms a matrix that supports and connects other tissues and organs. Below is an overview of its components:
===Components of Connective Tissue===
Connective tissue it consist 3 types of components:


''''''1) Cells of connective tissue'''''
* Cells
:*Fibroblasts
** Resident (fixed)
** Transient (wandering)
* ECM
** Fibers
** Amorphous ground substance


:*Adipocytes
Connective tissue types belong to three main categories:


:*Macrophage and Mononuclear Phagocyte System
* Connective tissue proper
** loose
** dense irregular
** dense regular
** elastic
* Embryonic connective tissue
** mesenchyme
** mucoid
* Specialized connective tissue
** reticular
** adipose
** cartilage
** bone
** blood


:*Mast Cells
== Types of the cells of connective tissue ==


:*Plasma Cells
=== Fixed cells ===
Reside within connective tissue. Derived from mesenchyme.


:*Leucocytes
==== Fibroblasts ====
Fibroblasts function in synthesis and degradation of the ECM. Therefore, DNA is in euchromatin form, and the RER and Golgi apparatuses are abundant. Fibro''cytes'' are "retired" fibroblasts that do not synthesize much.


'''2) Fibers of connective tissus'''
==== Reticular cells ====
Similar to fibroblasts, produce reticular fibers. N<small>ote: Reticular cells ≠ reti</small>culocytes! Reticulocytes are immature RBCs.


:*Collagen
==== Adipocytes ====


:*Reticular fibers
* '''Univacuolar'''
** spherical cell
** one large vacuole (stores triacylglycerols) takes up most of the space
** cytoplasm, flattened nucleus and other organelles are pushed to the periphery of the cell
** major component of <u>white</u> adipose tissue
*** energy storage
*** also functions in hormone production (adipokinins, leptins)
*** highly vascularized
* '''Multivacuolar'''
** multiple smaller fat droplets
** nucleus is more central
** burns fat to heat via mitochondria, functions in thermoregulation
** major component of <u>brown</u> adipose tissue
*** more abundant in fetuses, neonates and small children
*** found primarily between scapulae, in axilla, mediastinum, and retroperitoneum


:*Elastic fibers
==== Pigment (melanin) cells ====


'''3)Ground substances of connective tissue'''
* irregularly shaped
* arise from ''neuroectoderm'' rather than mesenchyme
* synthesize and store melanin


Connective tissue is mostly consisted by ECM=Extracellular matrix and  not from cells like other tissues.
Schematic comparison of all fixed cells [[wikiskripta:Soubor:Buňky_fixní.jpg|here]].
Extracellular matrix consists of :
:*protein fibers
:*collagen
:*reticular fibers
:*elastic fibers
:*ground substance
:*anionic macromolecules:
:::• glycos-aminoglycans
:::• proteo-glycans
:*multi adhesive glycoproteins:
:::• laminin
:::• fibronectin  (That stabilizes the ECM by binding to the receptor proteins  integrins on the surface of cells)


===Role:===
=== Wandering cells ===
- structural
Formed in red bone marrow from hemocytoblasts, enter connective tissue via bloodstream.
-      biological= a reservoir of factors that controls the growth and the differentiation
- Medium in which nutrients and metabolic wastes are exchange between cells and their blood supply ( due  to its hydrated nature)


===Origin:===
==== Macrophages ====


Mesenchyme (Mesenchymal cells)
* variable shape with protrusions
 
* kidney-shaped nucleus
- develops from the mesoderm (middle layer of the embryo)
* phagocytose debris, damaged, or foreign cells  
* mainly in sparse connective tissue along capillaries


- migrate from their site of origin surrounding all developing organs
==== Plasma cells ====


- develops into other types of structure such as:
* eccentrically placed nucleus, alternating heterochromatin and euchromatin
* large amount of cytoplasm and RER (intensive proteosynthesis)
* synthesize IgE, which binds to antigens
* usually in places where bacteria and foreign substances easily enter the body


:* blood cells
==== Mast cells ====
:* endothelial cells
:* muscle cells


=='''CELLS OF CONNECTIVE TISSUE'''==
* large, ovoid shape
* occur in the sparse collagen ligament of GIT and respiratory mucosa
* mediate allergic reaction
*# receptors bind to IgE
*# basophilic secretory granules with histamine and heparin released
*# inflammation in surrounding tissue


The connective tissue is consisted of many different cells with different origin and different function as:
Schematic comparison of wandering cells [[wikiskripta:Soubor:Bloudivé_buňky.jpg|here]].


==='''Fibroblasts'''===
== Extracellular Component ==
-Fibroblasts originate from Mesenchymal cells ,are the most common cells in connective tissue, and spend all their life to connective tissue.


-Synthesize:
=== Fibers ===


:* collagen
==== Collagen ====
Collagens include a family of proteins categorized into three main categories (fibril-forming, network forming, and anchoring). They are made up of individual fibrils of tropocollagen polymers. The thickness varies depending on the type.


:* elastin
The most well-known types and their locations are listed below. Mnemonic: '''B'''e '''S'''o '''T'''otally '''C'''ool, '''R'''ead '''B'''ooks!


:* glycos-aminoglycans
* '''collagen I''' ('''B'''one, '''S'''kin''', T'''endons)
** ~1.5 nm diameter and 300 nm long
** most abundant
** 67 nm periodicity
* '''collagen II''' ('''C'''artilage - hyaline and elastic)
* '''collagen III''' ('''R'''eticulin of reticular fibers)
* '''collagen IV''' ('''B'''asal lamina)


:* proteo-glycans
Synthesis of collagen type I (most studied):


:* multi-adhesive glycoproteins
# '''procollagen α''' chains produced by ribosomes in RER and imported into cisternae
# Hydroxylases modify some AAs, requiring O<sub>2</sub>, Fe<sup>2+</sup>, and <u>Vitamin C</u>
# three α chains are aligned, linked by disulfides, and folded into a '''triple helix'''
# triple helix is exocytosed and cleaved into '''procollagen''' (basic subunit which is differently assembled into different types of collagen)
# procollagen is converted to collagen molecules, which self-assemble into polymeric collagen (this is driven by entropy)
# Lysyl oxidase cross-links collagen molecules to further stabilize structure


-Have two stage of activity and they can be differentiated microscopically:


* '''fibroblast = active cell'''
Schematic of synthesis [https://upload.medbullets.com/topic/102078/images/collagen.jpg here]


::- large cell
Collagen is acidophilic and typically stains pink.
::- ovoid, large, pale-stain  nuclei with fine chromatin,
::- prominent nucleolus
::- Basophilic, abundant, irregular cytoplasm,
::- rich in rough ER,
::- and well developed App. Golgi


* '''fibrocyte  = dormant cell'''
==== Elastin ====


::- small cell
* 2 μm diameter elastic fibers
::- smaller and heterochromatic , darker , elongated nuclei,
* composed of fibrillin scaffolds embedded in elastin network
::- more acidophilic cytoplasm with less RER
* secreted by <u>fibroblasts</u>
::-Are targets of various growth factors that influence growth and differentiation!
* found interspersed with collagen in locations subject to tensile or shear stress, as well as in elastic lamellae
* allows structures to return to original shape


==== Reticular fibers ====


====Medical application:====
* 0.5-2 μm diameter
* consist mostly of collagen type III
* found in reticular connective tissue
** hematopoietic tissue (bone marrow and spleen)
** lymphatic tissue
** surrounds adipocytes, smooth muscle, nerve fibers, small blood vessels


The regenerative capacity of connective tissue  is responsible for repairing destroyed tissues:
=== Ground substance ===
Ground substance is a highly-hydrated space-filler between cells and in the ECM. It consists mainly of three different types of molecules


'''Scar''' is formed by connective tissue (CT) after traumatic or inflammation injury.
* '''glycosaminoglycans''' (GAGs) aka mucopolysaccharides
** long polymers of repeating disaccharide units
** often sulfated
** ex: <u>hyaluronic acid</u>, chondroitinsulfate, keratansulfate
* '''proteoglycans''' and their aggregates
** consist of a core protein with covalently bond sulfated GAGs (predominant part)
** e.g. aggrecan (in cartilage), perlecan (in basal lamina)
* '''glycoproteins'''
** consist of a protein core with branched oligosaccharide chains
** e.g. fibronectin, <u>laminin</u>


'''Healing of surgical incisions''' depends on reparative capacity of Connective T:
== Connective tissue proper ==


::* The fibrocyte reverts to the fibroblast state
=== Dense collagen connective tissue ===


::* The myofibroblast, a cell with features of both fibroblast and smooth muscle cell plays a basal role in''' “wound contraction”.'''
* dominant fibrillar component, cells (mostly fibroblasts) rare
* collagen fibers arranged to paralell or interlaced bundles
* regular dense collagen c.t. (tendons)
* irregular dense collagen c.t. (capsules of organs, sclera)


::* Myofibroblasts  have most of the morphological characteristics of fibroblasts but contain a big quantity of Actin microfilaments and myosin responsible for the wound healing
{| class="wikitable"
|+
!Connective Tissue Proper
!Composition
!Structure
!Locations
|-
|Loose (areolar)
|ground substance and many cells
|randomly distributed fibers (much GAGs, elastic fibers, some collagen I&III)
|stroma in epithelial organs, lamina propria of tunica mucosa, tela submucosa, tunica adventitia and organ interstitium
|-
|Dense regular
| rowspan="2" |few cells (mostly fibroblasts), mostly collagen
|parallel collagen fibers
|ligaments, tendons, aponeuroses, stroma of cornea
|-
|Dense irregular
|randomly arranged collagen fibers
|dermis, capsules of organs, sclera, GIT submucosa
|}


== Embryonic connective tissue ==


==='''Adipocytes'''===
=== Mesenchyme ===
-They are connective tissue cells, special storage of neutral fats and the producers of heat. They are called''' fat cells'''.
<gallery>
File:Tecido adiposo multilocular brown adipose tissue.gif|
</gallery>


=== Macrophages and mononuclear phagocyte system'''===
* mostly a matrix of collagen fibers with undifferentiated cells (both components are sparse)
-Originate from hematopoietic stem cell in bone marrow, circulate in the blood and after move into connective tissue where remain and execute their function
* has progenitor cells for all adult connective tissue
-They have different morphology, different name and different function in base of their location in specialized tissue:
* found in embryonic mesoderm
*'''in connective tissue = Macrophages '''.
:* '''defense cells'''and produce chemotactic factors, cytokines and several enzymes. In case of inflammation macrophages are stimulated and are arranged in clusters forming epithelioid cells (they look like epithelial cells). Change their morphological characteristics and metabolism becoming activated with increase capacity of phagocytosis.
: * ''' antigen-presenting cells'''. They have class II MHC molecules in their surface. The CD4 Helper lymphocytes are activated by the presentation of antigen on Class II MCH molecule and proliferate by mitosis. The daughter T-cell lymphocytes activate the B cells that also proliferate by mitosis and after that differentiate into plasma cells. These plasma cells secrete specific antibodies for the antigen presented.
*'''in blood=monocytes'''.  They  are precursors of macrophages. Usually are increasing in viral infections.
*'''in Liver=Kuppfer cells'''  They are macrophages.
* '''in nerve tissue and central nervous system=Microglia cell'''. They are Macrophages.
*'''in Lymph nodes=Dendritic cells'''. They are Antigen presenting cells and are important in immune respond
*'''in Skin=Langerhans cells'''.They are Antigen presenting cells.
*'''in Lungs'''. They help clean up the lungs.
<gallery>
File:Macrophage in the alveolus Lung - TEM.jpg|Macrophage in the alveolus lung
</gallery>


==='''Mast cells'''===
=== Mucoid ===
Masts cells originate from '''Hematopoietic stem cell,''' the progenitor cell in Bone marrow. This progenitor circulates in blood, cross the wall of venules and capillaries and they penetrate the connective tissue where they proliferate and differentiate. They are not found in blood. They are large oval or round connective tissue cells. Their cytoplasm is filled with basophilic secretory granules containing paracrine compounds that promote local inflammatory response as:
:* histamine – acts in allergic reaction.
:* heparine –acts locally as anticoagulant
:* serine proteases- activate various mediators of inflammation
:* eosinophil and neutrophil chemotactic factors. In special conditions as in anaphylactic reactions Eosinophil chemotactic factor attracts eosinophils in phase of allergic reaction.
:* leucotrienes C4, D4, SRS-A=Slow Reacting Substance of Anaphylaxis
The granules display metachromasia=they can change color of some basic dyes (ex.toluidine blue) from blue to purple or red. This happens due to the high content of acidic radicals in their glycosaminoglycans and they are poorly preserved by common fixatives (usually mast cells are difficult to identify).
The small, central, spherical nucleus is usually obscured by the cytoplasmic granules
Specific locations of masts cells:
-'''Perivascular masts cells''' are near small blood vessels in skin and mesenteries.
-'''Mucosal mast cells''' in mucosa lining in digestive tract and in respiratory tract
<gallery>
File:Mast cell.png|Mast cell
</gallery>


====Medical application====
* originates from extra-embryonic mesoderm
'''Anaphylactic shock''' is an immediate hypersensitive reaction.
* random fibroblasts and collagen embedded in matrix of hyaluronic acid and GAGs (chondroitinsulfate)
It occurs very quickly, within a few minutes, after penetration by an antigen of an individual previously sensitized. When the allergen (antigen) enters for the first time in the organism , plasma cell produce a specific IgE ( immunoglobulin or antibody contra the specific allergen) that is bound to the surface of a Mast cell. When a second exposure to the same antigen occurs, these are bind to IgE on mast cell which is activated leading to degranulation. Liberated histamine causes contraction of smooth muscle mainly in the bronchioles, and dilates and increases the permeability of capillaries. Due to the action of histamine are the symptoms of dyspnea and blushing that appear in this condition. The Eosinophil Chemotactic Factor of Anaphylaxis attracts blood Eosinophils. So in this condition in the full blood count characteristically appears eosinophilia (absolute number of eosinophils more than 800). Due to the fact that mast cells are abundant in skin, respiratory and digestive system the mainly symptoms in anaphylactic shock are concentrated initially at these areas.
* ex: Wharton's jelly


==='''Plasma Cell'''===
== Specialized connective tissue ==


'''Morphology'''
=== Elastic connective tissue ===
*Are large ovoid cells
*With basophilic cytoplasm due to rich RER
*eccentrically placed, not central nucleus
*Nucleus is  spherical with an appearance of «clock-face»
*Juxtanuclear Golgi apparatus + centriole ( pale region of the cell)
*Normal there are a few plasma cell in most connective tissue.
*Their life spasm is only 10-20 days.


===='''Medical application'''====
* high amount of elastic fibers arranged in parallel, with a few collagen fibers
* '''Immune respond to an antigen'''. Plasma cells are derived from B Lymphocytes and are responsible for synthesis of imunoglobulins. These are the antibodies that are produced after the penetration of a bacterium or (in general) an antigen the organism. Each antibody is specific for each antigen.
* sparse cells
* '''Malignant transformation''' of plasma cells leads to Monoclonal Plasma cells. These are cells that secrete a monoclonal immunoglobulin. When these monoclonal plasma cells represent  more than 30% of the total bone marrow cells  produce the hematological disease named Multiple myeloma with characteristic bone lytic lesions.
* ex: ligamenta flava of spine and other elastic ligaments, elastic membranes of arteries


=== Leucocytes ===
=== Reticular connective tissue ===
Originate from hematopoietic stem cell in the bone marrow, move to the connective tissue where they reside for a few days. They are transient cells of most connective tissue and usually die by apoptosis. Leukocytes migrate from the blood vessels by diapedesis. Diapedesis is increased during inflammation (defensive reaction against foreign substances or bacteria). Sings for inflammation are redness, swelling, heat and pain. Leucocytes do not return to the blood after arriving in connective tissue except lymphocytes.


==''' FIBERS OF CONNECTIVE TISSUE'''==
* reticular fibers produced by fibroblasts
* provides supporting scaffold and attachment site for immune cells
* found in bone marrow, secondary lymphatic organs, and some other tissues


==='''Collagen'''===
=== Adipose tissue ===
Primarily made up of adipocytes (see above description)


-It is a family of proteins!
=== Cartilage ===
Cartilage is a type of connective tissue that offers resistance yet is flexible and [https://en.wikipedia.org/wiki/Resilience_(materials_science) resilient]. 


-The most abundant protein in human body (30% of the body weight)
The dominant constituent is ground substance, while collagen and elastic fibers are found in various proportions, depending on the type.


-We have more than 20 types of collagen in function of the degree of rigidity, elasticity and strength the cell type  (which produce the collagen), the molecular composition, the morphological characteristics, function and distribution.
It is avascular, so nutrition has to be provided via diffusion from the synovial fluid or through the perichondrium.


====''' Classification''' ====
The main cells are
'''According to their structure + Function are classified in 4 categories:'''


'''1) COLLAGEN that form FIBLILS (Visible by optical microscopy)'''
* '''chondroblasts'''
** actively synthesize cartilage matrix (ground substance, collagen and elastin)
** therefore, DNA is in euchromatin form, RER and Golgi app. are abundant
** cells group together in isogenous groups, chondrons, and territories
** spindle-shaped cells closer to perichondrium, spherical shape further away
* '''chondrocytes'''
** decreased synthetic activity but function in maintenance


*Type I     -Skin, Tendon, Bone, dentin        -Resistance to tension
Elastic and hyaline cartilage are encapsulated by '''perichondrium''', which is a layer of dense connective tissue. It has two layers:


*Type II        -Cartilage, vitreous body         -Resistance to pressure
* fibrous layer
** contains dense irregular connective tissue with elastic fibers and fibroblasts
** functions in protection
** rich vascularization and innervation for chondrogenic layer below
* chondrogenic layer
** hosts mesenchymal cells, which proliferate and differentiate to chondroblasts
** important in cartilage production


*Type III      -Skin, muscle, blood vessels        -Structural maintenance in expansible organs
==== Classifications of cartilage ====
Schematic of the arrangement of cartilage cells and matrix in the individual types of cartilage can be found [http://histologie.lfp.cuni.cz/education/Web_histo_schemata/eng/chon/imgs/cartilago1.jpg here].


*Type V        -Fetal tissues, Skin, bone          - Participate in type I  Collagen function
===== Hyaline =====


*Type XI        - Cartilage                 - Participate in type II Collagen function
* consists of type II collagen and aggrecan
* cells are alone or in isogenous groups, embedded within basophilic territorial matrix
* can provide
** structural support (in fetal skeleton, ribs, respiratory tract)
** smooth surface for articulations


The molecules of this collagen:
Scheme of the developing hyaline cartilage can be found [http://histologie.lfp.cuni.cz/education/Web_histo_schemata/eng/chon/imgs/cartilago2.jpg here]. Note the basophilic territorial matrix (due to a higher concentration of proteoglycans), while the interterritorial matrix is acidophilic


:*aggregate to form fibrils clearly visible in optical microscopy
===== Elastic =====


:*collagen type I is the most abundant in organism
* consists of aggrecan and more noticeable fibrous component (type II collagen and elastic fibers)
* cells are regularly dispersed
* can provide
** structural support of soft tissues (epiglottis and small laryngeal cartilages)
** offer flexibility (external ear)


:*make the structures of the tissues named '''“ collagen fibers”''' forming tendons, organ capsules and dermis
===== Fibrocartilage =====
<gallery>
File:Fibers of Collagen Type I - TEM.jpg|Collagen type I
</gallery>


* consists mostly of type I collagen with some type II
* isolated chondrocytes, also has fibroblasts
* resistant to compression, shearing, and tension (intervertebral discs, menisci, pubic symphysis, tendon insertions)


'''2) FIBRIL associated COLLAGENS ( Not visible detected by immunochemistry)'''
=== Bone ===


*Type IX    - Cartilage, vitreous body      -Bound glycos-aminoglicans and is associated with Collagen type II
==== Structure ====
solid c.t. composed of mineralized ECM


*Type XII  - Embryonic tendon, Skin      -Interacts with type II collagen
unique biomechanical properties


*Type XIV-Fetal skin, tendon
* periosteum
 
** outer bone layer of dense irregular collagen c.t.
These types of collagens:
** Sharpey’s(perforating) fibers
** inner layer of osteoblasts and osteoprogenitor cells
* endosteum
** thin layer of bone lining cells on inner surface
** osteoblasts, osteoprogenitor cell


:*Are short structures
8. Draw the localization and histological structure of periosteum and endosteum in an idealized scheme of a bone (e.g. femur, humerus). Where are the Sharpey’s fibers located?


:*That binds the surface of collagen fibrils to one another and to other component of the ECM
===== Cells =====


:*Are also known as''' FACIT: Fibril Associated Collagens with Interrupted Triple helices'''
* '''osteoblasts'''
** approx. cuboidalcells, localizedon innerand outerbone surface
** euchromatin-richnucleus, abundant rER and Golgi apparatus
** synthesis of organic matrix (osteoid) and collagen fibers
** mineralization
* '''osteocytes'''
** localized in lacunae in mineralized bone matrix
** connected by cytoplasmic processes through canaliculi ossium
** local bone remodelling
* '''osteoclasts'''
** localized on bone surface in resorption bays (Howship’s lacunae)
** large, multi-nuclear cells (50-100 μm)
** complex ultrastructure of plasma membrane (ruffled border)
** origin by fusion of monocyte-macrophage progenitors
** resorption of bone tissue


9. Graphically schematize principal ultrastructural hallmarks of osteoblasts, osteocytes and osteoclasts. What is the origin of these cells?


'''3) COLLAGEN that forms ANCHORING FIBRILS ( not visible detected by immunochemistry)'''
===== Matrix =====
bone lamellae


*Type VII  -Epithelia -Anchors skin, epidermal basal lamina to underlying stroma
* parallellayers of mineralized ground substance
* collagen I fibrils (3-5 μm) highly oriented in similar direction
This type of collagen:
* hydroxyapatite
* contains other proteins with structural or metabolic functions (e.g. osteocalcin, osteonectin, osteopontin, bone sialoprotein)


:*Bind the basal lamina to reticular fibers in the underlying connective tissue
==== Bone tissue types ====
Classify principal histological types of bone tissue (fibrillar and lamellar), and graphically schematize arrangement of mineralized collagen fibers in individual types. What method can be used for preparation of bone slide?


'''Primary bone''' (woven, fibrilar)


'''4) COLLAGEN that forms NETWORKS (not visible detected by immunochemistry)'''
* collagen fibers interlaced via no particular structural pattern
* bone cells dispersed rather randomly
* developmentaly primitive


*Type IV  – All basement membranes    - Support of delicate structures and - Filtration
'''Secondary bone (lamellar)'''


This type of collagen *constitutes the major structural component of basal lamina
mineralized ground substance and collagen fibers form lamellae


===='''Synthesis'''====
* '''trabecular (spongy) bone'''
Collagen synthesis can be done in different cells as fibroblast, chondroblast, osteoblast and odontoblast.
** sheet lamellae parallel to surface form trabecules (~300 μm)
*In ribosome on RER is produced the procollagen '''“a chain”'''
** avascular, nutrition by diffusion from bone marrow
* This is intertwine (πλέκεται) to make triple helices and held together by hydrogen bonds and hydrophobic interactions
* '''compact bone'''
*Every third amino-acid in “a chain” is''' glycine'''
** Haversian systems (osteons, 100-400 μm) of 5-20 bone lamellae concetrically arragend around Haversian canal
*Two other small amino-acids abundant in collagen are hydroxylated and form '''hydroxyproline''' and '''hydroxylysine.'''
*** Haversian canals (~20 μm) with capillaries or postcapillary venules and occasional c.t. and nerve fibers, lined by endosteum
*The 3 “a chain” forms a '''rod-like procollagen molecule''' and can be:
*** transverse Volkmann canals
:'''-homotrimetric'''  = when the 3 “a chain” are  identical
** circumferential lamellae - external and internal
:'''-heterotrimetric''' = when the 2 or all 3 “a chains” different
** interstitial lamellae – inactive, remodelled osteons


*In collagen I, II and III the procollagen molecules are aggregate and become packed together forming '''FIBRILS'''
7. Draw the structure of Haversian systems in compact bone and indicate localization of Volkmann’s canals
'''Collagen fibrils:'''
*are thin, elongated structures with diameter =20-90 nm
*have transverse striations with periodicity (64-68nm)
*this is caused by the regular overlapping arrangement of the collagen molecules


-In some collagen types (V, XI) fibrils associate further with''' FACIT''' collagen to form''' FIBERS'''
==== Joints ====
Bones join each other at joints. Joints can be classified according to the freedom of motion that they allow.


-In collagen type I the fibers can form large '''BUNDLES'''
'''Diarthroses''' allow free movement of the bones. An articular capsule encloses the joint and the synovial fluid within. The outer layer of the capsule consists of a fibrous layer. The '''synovium''' forms the inner layer of the articular capsule (as well as bursae and tendon sheaths). It is well-vascularized and innervated. It can be further divided into two layers: ''subintima,'' which consists of connective tissue, and ''intima'', which has thin folds extending into the joint cavity and cuboidal cells with microvilli.


-In collagen type II (present in cartilage) the fibrils '''does NOT''' form fibers or bundles
The '''synovial fluid''' itself is high in hyaluronans, serves in the exchange of gases, nutrients and wastes, and allows for the passage of leukocytes.


-Collagen type IV (present in all membranes) assembles as a '''lattice-like network''' in the basal lamina
'''Synarthroses''' severely limit movement. These include fibrous and cartilaginous joints. These include synostoses, syndesmoses, and symphyses


==== Bone ossification ====
differentiation of osteoprogenitor cells and osteoblasts from mesenchymal stem cells


Microscopic examination:
* intramembraneous ossification
-In spite of «the fresh collagen fibers» are colorless strands, when appears in increased numbers for ex. In tendons, they appear''' white'''
** formation of osteoid and direct ossification without cartilage model
-In the light microscope collagen fibers are acidophilic and they stain:  
* endochondral ossification
*'''Pink''' with Eosin
** hyaline cartilage model, e.g. growth plate
*'''bleu''' with Malory trichrome stain
* typical zonation (mnemonic: real people have career opportunities)
*'''green''' with Masson trichrome stain
** reserve cartilage
*'''red''' with Sirius red
** proliferating cartilage
** hypertrophic (maturing) cartilage
** calcifying cartilage - line of erosion
** ossification and remodelling


12. Describe the difference between membranous and chondrogenic ossification. 13. Graphically schematize the growth plate with complete zonation. By using any information resource explain, why the growth plates close after the puberty. What is the principle of bone age determination in clinical or forensic practice?


===='''Medical application'''====
==== Bone remodelling ====
*'''Osteogenesis Imperfecta'''= A mutation in a single amino acid for example in glycine in colagen type I. Patients show spontaneous fractures and cardiac insufficiency
10. Draw a graphical scheme of bone remodeling. 11. By using any information resource decipher what is the histological background of osteoporosis, and why osteoporosis typically develops after menopause?
*'''Progressive systemic sclerosis'''= over accumulation of collagen (fibrosis).  
*'''keloid'''= local swelling in the place of scars of the skin
*'''Scurvy'''= Deficiency of Vit C is characterized by degeneration of connective tissue. In Vit C deficiency the fibroblasts synthetize defective collagen (In the hydroxylation of prolyne) Symptoms are loss of teeth and bleedings. Treatment by fresh food, particularly citrus fruit rich in vitamin C.


==='''Reticular fibers'''===
== References ==
Mescher, A. and Junqueira, L., 2018. ''Junqueira's basic histology''. New York: McGraw-Hill, pp. 96-159.


Reticular fibers are consisted mainly by collagen type III and forms thin and extensive network around the parenchymal cells of various organs for example liver and endocrine gland and in Hematopoietic organs  for example spleen, lymph nodes, red bone marrow.  
Vaňhara, Petr et al. ''Guide To General Histology And Microscopic Anatomy''. 1st ed., Masaryk University Press, 2020, pp. 7-9.
 
__INDEX__
They are NOT visible in H&E heamtoxyline& Eosin preparation. They are stained BLACK by '''silver salts''' and are also called '''argyrophilic'''. They are also '''PAS positive'''.
 
==='''Elastic Fibers'''===
Elastic fibers re thinner than the average collagen fiber, form sparse networks interspersed with collagen bundles in many organs as the wall of large arteries. he major functional property is to give elasticity to the organs.
Developing of E.F is made in 3 stages:
 
'''1) First stage:'''
*Fibrillin: a large glycoprotein  formed from a core of 10-nm microfibrils
*Fibrillin binds Elastin = forms scaffolding (σύστημα σκαλωσιάς) necessary for deposition of elastin
*Microfibrils and fibrillin alone are used in some organs such as to hold in place the lens of the eye.  Such Microfibrils are not elastic but are highly resistant to
pulling forces
:* Defective fibrillin = leads to th eproduction of fragmented elastic fibrils
'''2) Second Stage:'''
*deposition of elastin between microfibrils forming larger fibers
*Elastin molecules:
:-are globular and
:-are secreted by '''fibroblasts''' in connective tissue and by  '''smooth muscle cells''' in walls of blood vessels
:-are rich in '''glycine''' and '''prolyne''' with many regions
:-polymerize to form fibers or sheet-like structures
:-contains 2 amino acids '''desmosine''' and '''isodesmosine''' which are produced when '''cross-links''' are formed among '''4 lysine residues''' in different elastic molecules
:-cross-links formed in lysine residues are catalyzed by '''lysil oxidase'''
:-is resistant to digestion by most proteases
:-is easily hydrolyzed by  '''pancreatic elastase''' 
'''3) Third stage:'''
Mature elastic fibers is produces by accumulation of elastin, which further surrounded by a thin sheath of microfilaments
* '''Elastic lamellae'''= in the wall of large blood vessels, elastin occurs as a '''fenestrated sheet''' named elastic lamellae or elastic sheet
* '''Microfibrils of fibrillin''' in some organs are used alone as in''' eye''' to hold in place the lens
'''Microscopic examination'''
Elastic fibers is difficult to be demonstrated by H&E.They are demonstrated with '''Aldehyde Fuscin''' which stains elastin a''' dark magenta'''
 
===='''Medical application'''====
'''Syndrom Marfan:''' mutation in the fibrillin gene, the protein that produce the scaffolding necessary for elastin. Patient with Syndrome Marfan
is tall and thin. His tissues are not resistant (lack of the resistance in tissue rich in elastic fibers) and his big vessels like aorta usually have aneurysm that is very dangerous to be dissected.
 
=='''GROUND SUBSTANCES'''==
The ground Substance of ECM is a complex mixture of macromolecules glycos-aminoglycans (GAGs), proteo-glycans and multi adhesive glycoproteins. This transparent mixture fills the space between cells and fibers and acts as lubricant and barrier to the penetration of invaders
==='''Glycos-aminoglycans (GAGs)'''===
The GAGs originally called mucopolysacharides and formed from repeating disaccharide units composed from:
- Hexozamine + Urotic acid
:'''Hyaluronic acid''' is the most ubiquitous GAG with a molecular weight from 100-1000KDa
Is a long polymer of a disaccharide glucosamine-glucuronate and is synthesized directly into ECM by the enzyme hyaluronate synthetase located in the membrane of many cells.This binds a big amount of water giving it a role in diffusion of molecules in connective tissue and in lubricating various organs and joints.is found in umbilical cord, synovial fluid, vitreous humor, and cartilage.
:'''All other GAGs''' are much smaller 10-40kDa and they are attached to proteins (Proteo-glycans). They are rich in sulfate and are intense hydrophilic and viscous.
==='''Proteo-glycans ''' ===
Proteoglycans are composed of a core protein + GAG/s, are synthetized on RER, mature in Golgi and secreted from cells by exocytosis
The main differences between Proteoglicans and Glycoproteins are:
* Proteoglycans:
:-Contain a core protein as a vertical rod
:-GAGs are covalently bound
:-GASs are unbranched polysaccharide
:-Contain a greater amount of carbohydrate (Than glycoproteins)
:-Can be pictured as a “test tube brush”
* Glycoproteins:
:-Are globular protein molecule
:-Chains of monosaccharides are covalently attached
:-Polypeptide content is greater than polysaccharide content
Proteoglycans are distinguished for their diversity and are proteoglycans of :
:* Extracellular Matrix (ECM) . Best example is '''Aggrecan''' :
-is one of the most important ECM proteoglycans
-Is the dominant proteoglycan in cartilage
-The core protein has several chondroitin sulfate and keratin sulfate chains
- And is bound via a link protein to hyaluronic acid
:* Cell Surface. Best example is '''Syndecan'''.
-Is a cell surface proteoglycan
-Is present on many types of cells , particularly epithelial cells
-The core protein spans the plasma membrane with a short cytoplasmic extension ->Heparan sulfate chains are attached to the extracellular extension
==='''Multiadhesive glycoproteins'''===
Multiadhesive glycoproteins have attached carbohydrates that are usually branched. The protein component predominates.  Its role is the adhesion of cells to their substrate
* '''1) Fibronectin''' Is synthetized by fibroblasts and epithelial cells. Its a dimeric molecule with binding sites for Collagens, GAGs and Integrins of cell membranes.For this reason is named Multiadhesive glycoprotein
* '''2) Laminin''' is  a trimetric cross-shaped glycoprotein with binding sites for collagen type IV,GADs and Integrins. This participate in adhesion of '''epithelium cells to basal lamina'''
* ''''3) Integrins = Matrix receptor'''.Are cell-surface molecule that bind to collagen, fibronectin and laminin.  These are '''transmembrane receptors ''' or  linker proteins and interact also with cytoskeleton ''' Actin microfilaments'''  in the presence of '''Talin''' and '''Vinculin'''.
These receptor connect the components of ECM (collagen, Fibronectin, Laminin) with the intracellular components (actin via Talin)
 
=='''TYPES OF CONNECTIVE TISSUE'''==
 
===''' Loose (Alveolar)'''===
*Is a very common type
*Has a delicate consistency and is flexible, well vascularized and not very resistant to stress
*Support many structures that are  normally under pressure
*Supports epithelial tissue in glands, in the mucous membranes and in peritoneal and pleural cavities.
*Forms a -layer around '''small blood and lymphatic vessels''' and papillary layer '''of dermis in hypodermis'''
*Fills the spaces between muscle and fibers
*Is also called areolar tissue (has all components of connective tissue in equal parts                                                                                                                     
 
===''' Dense'''===
*Offer resistant and protection
*Has the same components with the loose connective tissue  but '''Fewer cells''' and '''more collagen fibers'''
*Is less flexible
*Is more resistant to stress
*Is of two different type in function of orientation of collagen fibers:
::'''a. Irregular'''
-Fibers in '''bundles without orientation'''
-form a 3-dimentional network
-provide resistance to stress from all directions
-is found close associated with loose connective tissue
::'''b. Regular'''
-fibers in bundles  are arranged with''' linear orientation'''
-in the same direction with the exerted stress
-and offers great resistance to traction forces
-is found in tendons and ligaments
-due to the fact that are rich in collagen fibers are '''white and inextensible'''
-they have parallel closely packed bundles of collagen and
-a very small quantity of ground substance
-a few fibrocytes with elongated nuclei and sparse cytoplasm that is not revealed in H&E because it stains the same color with fibers
-The collagen bundles of tendons are '''enveloped''' by small amounts of '''loose connective tissue,''' with small vessels and nerves.
-are poorly vascularized so the repair of damage is very slow
-externally the tendon is surrounded by a '''sheath of dense irregular tissue'''
-Synovial cells of Mesenchymal origin form a sheath, from 2 layers.
-The space between these two layers is filled with fluid similar to the fluid of synovial joints rich in water, proteins,Hyaluronate  and other GAGs
-Acts as lubricant
 
===''' Specialized'''===
::'''a. Reticular connective tissue'''
*Is a 3-dimesnional network
*formed by reticular fibers of type III collagen
*produced by reticular cells ( specialized fibroblasts)
*heavily glycosylated reticular fibers provide the architectural framework for cell attachment
*is found in hematopoietic and lymphoid organs : bone marrow, Lymph nods, spleen
*the reticular cells are dispersed along this framework forming a''' spongelike structure''' in which cells and fluids are freely mobile
::'''b. Mucous connective tissue'''
*is found in the umbilical cord and fetal tissue
*has an abundant ground substance
*composed mostly of hyaluronic acid
*making it a jellylike tissue named '''Wharton’s Jelly (in umbilical cord)
* is found also in '''pulp cavity of young teeth'''
 
{{Cite
| type = book
| surname1 = Mescher
| name1 = Anthony L
| title = Jungueira's Basic Histology
| edition = 12th Edition
| year = 2010
| isbn = 978-0-07-163020-7
}}

Revision as of 00:00, 8 March 2022

Connective tissue forms a matrix that supports and connects other tissues and organs. Below is an overview of its components:

  • Cells
    • Resident (fixed)
    • Transient (wandering)
  • ECM
    • Fibers
    • Amorphous ground substance

Connective tissue types belong to three main categories:

  • Connective tissue proper
    • loose
    • dense irregular
    • dense regular
    • elastic
  • Embryonic connective tissue
    • mesenchyme
    • mucoid
  • Specialized connective tissue
    • reticular
    • adipose
    • cartilage
    • bone
    • blood

Types of the cells of connective tissue

Fixed cells

Reside within connective tissue. Derived from mesenchyme.

Fibroblasts

Fibroblasts function in synthesis and degradation of the ECM. Therefore, DNA is in euchromatin form, and the RER and Golgi apparatuses are abundant. Fibrocytes are "retired" fibroblasts that do not synthesize much.

Reticular cells

Similar to fibroblasts, produce reticular fibers. Note: Reticular cells ≠ reticulocytes! Reticulocytes are immature RBCs.

Adipocytes

  • Univacuolar
    • spherical cell
    • one large vacuole (stores triacylglycerols) takes up most of the space
    • cytoplasm, flattened nucleus and other organelles are pushed to the periphery of the cell
    • major component of white adipose tissue
      • energy storage
      • also functions in hormone production (adipokinins, leptins)
      • highly vascularized
  • Multivacuolar
    • multiple smaller fat droplets
    • nucleus is more central
    • burns fat to heat via mitochondria, functions in thermoregulation
    • major component of brown adipose tissue
      • more abundant in fetuses, neonates and small children
      • found primarily between scapulae, in axilla, mediastinum, and retroperitoneum

Pigment (melanin) cells

  • irregularly shaped
  • arise from neuroectoderm rather than mesenchyme
  • synthesize and store melanin

Schematic comparison of all fixed cells here.

Wandering cells

Formed in red bone marrow from hemocytoblasts, enter connective tissue via bloodstream.

Macrophages

  • variable shape with protrusions
  • kidney-shaped nucleus
  • phagocytose debris, damaged, or foreign cells
  • mainly in sparse connective tissue along capillaries

Plasma cells

  • eccentrically placed nucleus, alternating heterochromatin and euchromatin
  • large amount of cytoplasm and RER (intensive proteosynthesis)
  • synthesize IgE, which binds to antigens
  • usually in places where bacteria and foreign substances easily enter the body

Mast cells

  • large, ovoid shape
  • occur in the sparse collagen ligament of GIT and respiratory mucosa
  • mediate allergic reaction
    1. receptors bind to IgE
    2. basophilic secretory granules with histamine and heparin released
    3. inflammation in surrounding tissue

Schematic comparison of wandering cells here.

Extracellular Component

Fibers

Collagen

Collagens include a family of proteins categorized into three main categories (fibril-forming, network forming, and anchoring). They are made up of individual fibrils of tropocollagen polymers. The thickness varies depending on the type.

The most well-known types and their locations are listed below. Mnemonic: Be So Totally Cool, Read Books!

  • collagen I (Bone, Skin, Tendons)
    • ~1.5 nm diameter and 300 nm long
    • most abundant
    • 67 nm periodicity
  • collagen II (Cartilage - hyaline and elastic)
  • collagen III (Reticulin of reticular fibers)
  • collagen IV (Basal lamina)

Synthesis of collagen type I (most studied):

  1. procollagen α chains produced by ribosomes in RER and imported into cisternae
  2. Hydroxylases modify some AAs, requiring O2, Fe2+, and Vitamin C
  3. three α chains are aligned, linked by disulfides, and folded into a triple helix
  4. triple helix is exocytosed and cleaved into procollagen (basic subunit which is differently assembled into different types of collagen)
  5. procollagen is converted to collagen molecules, which self-assemble into polymeric collagen (this is driven by entropy)
  6. Lysyl oxidase cross-links collagen molecules to further stabilize structure


Schematic of synthesis here

Collagen is acidophilic and typically stains pink.

Elastin

  • 2 μm diameter elastic fibers
  • composed of fibrillin scaffolds embedded in elastin network
  • secreted by fibroblasts
  • found interspersed with collagen in locations subject to tensile or shear stress, as well as in elastic lamellae
  • allows structures to return to original shape

Reticular fibers

  • 0.5-2 μm diameter
  • consist mostly of collagen type III
  • found in reticular connective tissue
    • hematopoietic tissue (bone marrow and spleen)
    • lymphatic tissue
    • surrounds adipocytes, smooth muscle, nerve fibers, small blood vessels

Ground substance

Ground substance is a highly-hydrated space-filler between cells and in the ECM. It consists mainly of three different types of molecules

  • glycosaminoglycans (GAGs) aka mucopolysaccharides
    • long polymers of repeating disaccharide units
    • often sulfated
    • ex: hyaluronic acid, chondroitinsulfate, keratansulfate
  • proteoglycans and their aggregates
    • consist of a core protein with covalently bond sulfated GAGs (predominant part)
    • e.g. aggrecan (in cartilage), perlecan (in basal lamina)
  • glycoproteins
    • consist of a protein core with branched oligosaccharide chains
    • e.g. fibronectin, laminin

Connective tissue proper

Dense collagen connective tissue

  • dominant fibrillar component, cells (mostly fibroblasts) rare
  • collagen fibers arranged to paralell or interlaced bundles
  • regular dense collagen c.t. (tendons)
  • irregular dense collagen c.t. (capsules of organs, sclera)
Connective Tissue Proper Composition Structure Locations
Loose (areolar) ground substance and many cells randomly distributed fibers (much GAGs, elastic fibers, some collagen I&III) stroma in epithelial organs, lamina propria of tunica mucosa, tela submucosa, tunica adventitia and organ interstitium
Dense regular few cells (mostly fibroblasts), mostly collagen parallel collagen fibers ligaments, tendons, aponeuroses, stroma of cornea
Dense irregular randomly arranged collagen fibers dermis, capsules of organs, sclera, GIT submucosa

Embryonic connective tissue

Mesenchyme

  • mostly a matrix of collagen fibers with undifferentiated cells (both components are sparse)
  • has progenitor cells for all adult connective tissue
  • found in embryonic mesoderm

Mucoid

  • originates from extra-embryonic mesoderm
  • random fibroblasts and collagen embedded in matrix of hyaluronic acid and GAGs (chondroitinsulfate)
  • ex: Wharton's jelly

Specialized connective tissue

Elastic connective tissue

  • high amount of elastic fibers arranged in parallel, with a few collagen fibers
  • sparse cells
  • ex: ligamenta flava of spine and other elastic ligaments, elastic membranes of arteries

Reticular connective tissue

  • reticular fibers produced by fibroblasts
  • provides supporting scaffold and attachment site for immune cells
  • found in bone marrow, secondary lymphatic organs, and some other tissues

Adipose tissue

Primarily made up of adipocytes (see above description)

Cartilage

Cartilage is a type of connective tissue that offers resistance yet is flexible and resilient.

The dominant constituent is ground substance, while collagen and elastic fibers are found in various proportions, depending on the type.

It is avascular, so nutrition has to be provided via diffusion from the synovial fluid or through the perichondrium.

The main cells are

  • chondroblasts
    • actively synthesize cartilage matrix (ground substance, collagen and elastin)
    • therefore, DNA is in euchromatin form, RER and Golgi app. are abundant
    • cells group together in isogenous groups, chondrons, and territories
    • spindle-shaped cells closer to perichondrium, spherical shape further away
  • chondrocytes
    • decreased synthetic activity but function in maintenance

Elastic and hyaline cartilage are encapsulated by perichondrium, which is a layer of dense connective tissue. It has two layers:

  • fibrous layer
    • contains dense irregular connective tissue with elastic fibers and fibroblasts
    • functions in protection
    • rich vascularization and innervation for chondrogenic layer below
  • chondrogenic layer
    • hosts mesenchymal cells, which proliferate and differentiate to chondroblasts
    • important in cartilage production

Classifications of cartilage

Schematic of the arrangement of cartilage cells and matrix in the individual types of cartilage can be found here.

Hyaline
  • consists of type II collagen and aggrecan
  • cells are alone or in isogenous groups, embedded within basophilic territorial matrix
  • can provide
    • structural support (in fetal skeleton, ribs, respiratory tract)
    • smooth surface for articulations

Scheme of the developing hyaline cartilage can be found here. Note the basophilic territorial matrix (due to a higher concentration of proteoglycans), while the interterritorial matrix is acidophilic

Elastic
  • consists of aggrecan and more noticeable fibrous component (type II collagen and elastic fibers)
  • cells are regularly dispersed
  • can provide
    • structural support of soft tissues (epiglottis and small laryngeal cartilages)
    • offer flexibility (external ear)
Fibrocartilage
  • consists mostly of type I collagen with some type II
  • isolated chondrocytes, also has fibroblasts
  • resistant to compression, shearing, and tension (intervertebral discs, menisci, pubic symphysis, tendon insertions)

Bone

Structure

solid c.t. composed of mineralized ECM

unique biomechanical properties

  • periosteum
    • outer bone layer of dense irregular collagen c.t.
    • Sharpey’s(perforating) fibers
    • inner layer of osteoblasts and osteoprogenitor cells
  • endosteum
    • thin layer of bone lining cells on inner surface
    • osteoblasts, osteoprogenitor cell

8. Draw the localization and histological structure of periosteum and endosteum in an idealized scheme of a bone (e.g. femur, humerus). Where are the Sharpey’s fibers located?

Cells
  • osteoblasts
    • approx. cuboidalcells, localizedon innerand outerbone surface
    • euchromatin-richnucleus, abundant rER and Golgi apparatus
    • synthesis of organic matrix (osteoid) and collagen fibers
    • mineralization
  • osteocytes
    • localized in lacunae in mineralized bone matrix
    • connected by cytoplasmic processes through canaliculi ossium
    • local bone remodelling
  • osteoclasts
    • localized on bone surface in resorption bays (Howship’s lacunae)
    • large, multi-nuclear cells (50-100 μm)
    • complex ultrastructure of plasma membrane (ruffled border)
    • origin by fusion of monocyte-macrophage progenitors
    • resorption of bone tissue

9. Graphically schematize principal ultrastructural hallmarks of osteoblasts, osteocytes and osteoclasts. What is the origin of these cells?

Matrix

bone lamellae

  • parallellayers of mineralized ground substance
  • collagen I fibrils (3-5 μm) highly oriented in similar direction
  • hydroxyapatite
  • contains other proteins with structural or metabolic functions (e.g. osteocalcin, osteonectin, osteopontin, bone sialoprotein)

Bone tissue types

Classify principal histological types of bone tissue (fibrillar and lamellar), and graphically schematize arrangement of mineralized collagen fibers in individual types. What method can be used for preparation of bone slide?

Primary bone (woven, fibrilar)

  • collagen fibers interlaced via no particular structural pattern
  • bone cells dispersed rather randomly
  • developmentaly primitive

Secondary bone (lamellar)

mineralized ground substance and collagen fibers form lamellae

  • trabecular (spongy) bone
    • sheet lamellae parallel to surface form trabecules (~300 μm)
    • avascular, nutrition by diffusion from bone marrow
  • compact bone
    • Haversian systems (osteons, 100-400 μm) of 5-20 bone lamellae concetrically arragend around Haversian canal
      • Haversian canals (~20 μm) with capillaries or postcapillary venules and occasional c.t. and nerve fibers, lined by endosteum
      • transverse Volkmann canals
    • circumferential lamellae - external and internal
    • interstitial lamellae – inactive, remodelled osteons

7. Draw the structure of Haversian systems in compact bone and indicate localization of Volkmann’s canals

Joints

Bones join each other at joints. Joints can be classified according to the freedom of motion that they allow.

Diarthroses allow free movement of the bones. An articular capsule encloses the joint and the synovial fluid within. The outer layer of the capsule consists of a fibrous layer. The synovium forms the inner layer of the articular capsule (as well as bursae and tendon sheaths). It is well-vascularized and innervated. It can be further divided into two layers: subintima, which consists of connective tissue, and intima, which has thin folds extending into the joint cavity and cuboidal cells with microvilli.

The synovial fluid itself is high in hyaluronans, serves in the exchange of gases, nutrients and wastes, and allows for the passage of leukocytes.

Synarthroses severely limit movement. These include fibrous and cartilaginous joints. These include synostoses, syndesmoses, and symphyses

Bone ossification

differentiation of osteoprogenitor cells and osteoblasts from mesenchymal stem cells

  • intramembraneous ossification
    • formation of osteoid and direct ossification without cartilage model
  • endochondral ossification
    • hyaline cartilage model, e.g. growth plate
  • typical zonation (mnemonic: real people have career opportunities)
    • reserve cartilage
    • proliferating cartilage
    • hypertrophic (maturing) cartilage
    • calcifying cartilage - line of erosion
    • ossification and remodelling

12. Describe the difference between membranous and chondrogenic ossification. 13. Graphically schematize the growth plate with complete zonation. By using any information resource explain, why the growth plates close after the puberty. What is the principle of bone age determination in clinical or forensic practice?

Bone remodelling

10. Draw a graphical scheme of bone remodeling. 11. By using any information resource decipher what is the histological background of osteoporosis, and why osteoporosis typically develops after menopause?

References

Mescher, A. and Junqueira, L., 2018. Junqueira's basic histology. New York: McGraw-Hill, pp. 96-159.

Vaňhara, Petr et al. Guide To General Histology And Microscopic Anatomy. 1st ed., Masaryk University Press, 2020, pp. 7-9.

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