Introduction
========

Cells (chondrocytes) - 5%
------------------------------
ECM
-----
- Fibers
    - Collagen Type II (10-20%)
    - Other collagens IX, XI, VI, X
-Elastins
Ground substance
---------------------
- H20 (75%)
- Proteoglycans and glycosaminoglycans
     - aggrecan
     - Hyaluronan
     - Decorin, byglycan, fibromodulin, syndecan, lumican, superficial zone protein
- Glycoproteins
    - Cartilage oligomeric protein (COMP), laminin, lubricin, chondro-adherin
    - Cartilage matrix protein (CMP), cartilage matrix glycoprotein (CMGP), chondronectin, fibronectin, anchorin CII
- Degradative enzymes (matrix metalloproteinases)
- Extracellular ions

Structure
======
Layers
--------
- decreasing H20, collagen, increasing PG from superficial to deep
- I Superficial gliding zone: thinnest, collagen fibers parallel to resist shear; first to show OA
- II Middle transitional zone: fibers obliquely; II and III have chondrons: communities of 2-3 chondrocytes
- III radial zone: largest, resists load and distributes compression
- tidemark - acellular; boundary between calcified and uncalcified cartilage
- IV calcified zone: hydroxyapatite crystals, type X collagen

Collagen
----------
- 90% type II
- Type I not normally found, only following injury
- Type X: associated with cartilage calcification

Proteoglycans and glycosaminoglycans
--------------------------------------------
- responsible for most of the water content of cartilage
- gives compressive strength
- hydrophilic molecules
- GAG (chondroitin sulphate, keratan sulphate) bound by sugar bonds to linear core of protein
- Aggrecan is the predominant proteoglycan

Degradative Enzymes
-------------------------
- Matrix metalloproteinases
    - collagenases
    - stromelysins
    - gelatinases
    - membrane-associated metalloproteinases
- Tissue-induced metalloproteinase inhibitors (TIMPs)
    - acidic polypeptides
    - maintains avascular nature of cartilage

Ions
-----
- high sodium and potassium ion
- sulphate residues on PGs attract these ions
- calcium high in calcified zone

Glycoproteins
----------------
- macromolecules: tissue glue
- COMP --> binds to various matrix proteins
- lubricin - joint lubricant

Chondrocytes
----------------
- from MSCs
- articular and growth plate chondrocytes --> different terminal differentiation
- diffusion for cell nutrition
- joint loading important for nutrition

Function
======
- joint lubrication
    - low coefficient of friction (0.002), 30 x << joint replacements
    - lowered by fluid-film deformation, elastic deformation of articular cartilage, synovial fluid and efflux of fluid from cartilage
- shock absorption
    - 10x >> bone
    - diffuses load

Biomechanical properties
- creep
- sress relaxation
- anisotropic

Lubrication
-------------
- boundary lubrication
- fluid film lubrication
    - hydrodynamic lubrication
    - squeeze-film lubrication
    - Elastohydrodynamic lubrication --> main one during dynamic joint function
    - Weeping or self-lubrication
    - Boosted lubrication

Injury and healing
============
- superficial injuries (above tidemark) heal
- deep injuries --> hematoma, fibrin clot/ inflammation --> fibrocartilage
- infections --> hydrolysis of collagen and PGs, cells (--> release of lysosomal enzymes)
- OA
     - collagen disruption 
         --> PGs can attract more water
             - decreased Young's modulus --> decreased ability to bear load
         - loss of lubricant --> increased interfacial wear
         - fatigue wear and accumulation of microscopic damage
    - chondroitin/keratan sulphate ratio increases    

Treatment
=======
Non-operative
-----------------
Physical therapy
``````````````
- immobilization --> cartilage atrophy
- Salter (1989): CPM --> FT defects in rabbits

Oral visco-supplementation
``````````````````````
- Glucosamine
    - amino-monosaccharide sugar
    - naturally occuring component of the GAGs keratan sulphate andn hyaluronate
    - in-vitro inhibition of PG synthesis by IL-1 and suppressing the inflammatory response of neutrophils
    - some benefit in RCTs
    - 1500 mg/day
- Chondroitin
    - GAG

Intra-articular visco-supplmentation
``````````````````````````````
- MW: Low (Hyalgan), intermediate (Orthovisc), HMW (Synvisc)
- limited evidence - no good studies showing good results

Operative Treatment
------------------------
Abrasion arthroplasty
``````````````````
- turns cartilage defect into a 'deep injury'
- fibrocartilage healing

Autograft/mosaicplasty
```````````````````
- full thickness osteochondral grafts from superomedial margin of femoral notch 
   - most useful in medial compartment
   - less useful for patellar
- superceded by newer tissue engineering therapies

Allograft
````````
- mostly for malignant tumors
- cartilage is immunoprivileged tissue
- spore-forming organism infection

Periosteal/perichondrial mesenchymal stem cells
---------------------------------------------------------
- cambium layer
- type II collagen and high PGs seen in repair tissue
- no convincing reports of efficacy

Chondrocytes from mesenchymal stem cells
---------------------------------------------------
- bMSC isolation --> 3D matrix --> defect

Autologous chondrocyte implantation (ACI)
-------------------------------------------
- Brittberg (1994) 
- harvest --> ex vivo expansion --> collagen gel carrier
- reinserted and periosteal flap sutured
- newer MACI

Role of growth factors
---------------------------
- TGF, IGF-1, FGF --> chondrocyte proliferation
- IGF-1 stimulate collagen and PG production
- BMPs
- limited success in human trials


Viva Questions
==========
- What is the composition of articular cartilage?
- Draw the structure of articular cartilage
- How are the functions of articular cartilage? How is structure related to function?
- What pathological processes are involved in the develop of osteoarthritis?
- What are the different options available for treating cartilage defects?

Revisions
2013-02-12: Original notes transferred from Evernote