Biology of Articular Cartilage

OPBSMusculoskeletalPathology

Must Know

• Articular cartilage is hyaline cartilage. Elastic cartilage is in epiglottis and Eustachian tube.
• Fibrocartilage is in discs, knee menisci and over the mandibular condyle.
• Cartilage is avascular, aneural and alymphatic, fed by diffusion from synovial fluid and subchondral bone.
• Chondrocytes are the only cell type, derived from mesenchymal stem cells, with no cell to cell contact.
• SOX9 commits cells to the chondrocyte lineage.
• Chondrocytes make up about 1 to 5 percent of tissue volume.
• Chondrocytes rely on glycolysis in a hypoxic tissue, with oxygen falling with depth.
• Adult chondrocytes do not normally divide, so repair capacity is limited.
• Major matrix molecules are type II collagen and aggrecan.

Zones

Zone	Share of depth	Cells	Collagen	Function
Superficial	About 10 percent	Flat, highest density, make lubricin	Thin fibres parallel to surface	Lubrication, tensile strength, resists swelling
Middle (transitional)	About 10 percent	Rounded single cells	Random	Resists shear and compression
Deep (radial)	About 80 percent	Vertical columns of 5 to 8 cells	Thickest fibres, perpendicular, anchored in bone	Greatest compressive strength
Calcified	Thin layer below tidemark	Hypertrophic chondrocytes	Not described	Anchors cartilage to subchondral bone

• The tidemark is a thin wavy basophilic line between articular and calcified cartilage.
• Water is about 80 percent of wet weight at the surface and 65 percent deep.

More on cells and regional variation

• Femoral condyle cartilage holds about 23,674 chondrocytes per mm2.
• Weight-bearing femoral condyle cartilage is about 2.4 mm thick. Ankle cartilage is about 1.5 mm.
• The ankle superficial zone is less distinct. The deep zone is the most conserved between joints.
• Matrix content varies locally with individual gait pattern.
• Cartilage stem or progenitor cells have been found and may migrate to injury sites, but their origin is uncertain.
• The same cell makes and breaks down matrix, unlike bone with osteoblasts and osteoclasts.
• Vessels and nerves enter calcified cartilage from subchondral bone. Ingrowth may add to osteoarthritis pain.
• Cellularity is inversely related to cartilage thickness.

Matrix Regions Around the Cell

Region	Thickness	Content
Pericellular	2 to 4 µm	Type VI collagen nest, fibronectin, biglycan, perlecan
Territorial	5 to 10 µm	Thicker radial collagen bundles
Interterritorial	Rest of matrix	Large type II bundles (Benninghoff arcades), COMP

• The chondron is the chondrocyte plus its pericellular matrix, found in middle and deep zones.
• Stiffness rises outward. Chondrocyte is softest, then pericellular matrix, then surrounding matrix.

More on the chondron

• The pericellular matrix filters mechanical signals to the cell.
• The primary cilium links the cell to matrix through integrins and TRPV4 channels.

Collagens

Type	Share	Role
II	90 percent adult, 75 percent fetal	Main fibril, tensile strength. Three identical α chains from COL2A1
III	Over 10 percent in adult	Made with age. May bind a weakened type II network
VI	Under 1 percent	Pericellular nest forming the chondron
IX	1 percent adult, 10 percent fetal	Decorates fibril surface, bridges to other matrix molecules
X	Not given	Only in hypertrophic cartilage
XI	3 percent adult, 10 percent fetal	Template controlling lateral growth of type II fibrils

• Type II collagen half-life exceeds 100 years. Turnover after skeletal maturity is negligible.

More on collagen biology

• Type IIA marks chondroprogenitors. Type IIB predominates in adult cartilage.
• Collagens II, IX and XI form cross-linked heterotypic fibrils in developing cartilage.

Aggrecan and Proteoglycans

• Aggrecan is 95 percent of cartilage proteoglycan.
• Core protein of 220 to 250 kDa with globular domains G1, G2 and G3.
• Between G2 and G3 sit keratan sulfate and about 100 chondroitin sulfate chains.
• Ionised carboxyl and sulfate groups give fixed negative charge.
• G1 binds hyaluronan noncovalently, stabilised by 45 kDa link protein, forming aggregates over 200 MDa.
• Charges 10 to 15 Å apart repel, causing osmotic swelling that resists compression.
• Collagen resists tension and shear and restrains proteoglycan swelling.
• Aggrecan monomer half-life is 3.4 years. Free hyaluronan-binding fragments last 25 years.

Molecule	Point to remember
Perlecan	Heparan sulfate proteoglycan, presents FGF2 in pericellular matrix
Decorin	SLRP with one chondroitin or dermatan sulfate chain
Biglycan	SLRP with two chains
Fibromodulin	SLRP with up to five keratan sulfate chains
COMP (thrombospondin 5)	Pentamer gathering five collagen molecules, speeds fibril formation
Matrilin-1 and 3	Adaptors linking collagen and aggrecan
Lubricin (PRG4)	Boundary lubricant from superficial chondrocytes and synoviocytes

• Lubricin deficiency causes camptodactyly-arthropathy-coxa vara-pericarditis (CACP) syndrome.
• Joint articulation raises lubricin expression. Pure compression does not.
• Very low friction needs lubricin tethering hyaluronan, which binds phospholipids to form hydration layers.
• In osteoarthritis excess COMP blocks collagen binding sites and hinders fibril formation.

More on minor matrix proteins

• SLRPs regulate type VI collagen network assembly and are nonaggregating with short cores.
• Decorin and fibromodulin bind type I and II collagen.
• Matrilins carry von Willebrand factor A domains.
• Fibulin binds the aggrecan G3 domain.
• Tenascin-C rises sharply in osteoarthritis.
• Membrane receptors include syndecan, CD44 (hyaluronan) and integrins. Collagen binds discoidin domain receptors.
• Recombinant lubricin is being explored as an intra-articular treatment.
• Aggrecan shields collagen from collagenase. Aggrecan-depleted cartilage is fully degraded by MMP-1.

Breakdown in Disease

• ADAMTS-4 and ADAMTS-5 are the aggrecanases.
• Cleavage at Glu373 and Ala374 in the interglobular domain releases most of the GAG-bearing aggrecan.
• After aggrecan loss, collagen is cut by collagenases, mainly MMP-13.
• TGF-β maintains chondrocyte phenotype in health. Raised levels in osteoarthritis drive fibrosis and bone change.
• Fibronectin, tenascin-C and hyaluronan fragments activate toll-like receptors.
• Osteoarthritic cartilage holds up to 10 times more fibronectin. Its fragments induce MMP-13 and ADAMTS-4 and 5.
• A 32-amino acid aggrecan fragment signals through TLR2, driving catabolism and pain.

More on proteases and fragments

• Aggrecanases cleave the core protein at five sites.
• ADAMTS-4 cleaves matrilin-3. ADAMTS-7 and 12 cleave COMP.
• ADAM-8 makes specific fibronectin fragments.
• The 32-mer is cut at 374ARGS by ADAMTS-4 or 5 and at DIPEN341 by MMPs.
• Fibromodulin and COMP can activate complement.
• SLRPs signal through IGF-1 and EGF receptors and store TGF-β.
• ADAMTS-5 is a drug target in osteoarthritis.
• Matrix fragments in synovial fluid, serum and urine are candidate biomarkers.

Ageing Versus Osteoarthritic Cartilage

Feature	Ageing	Osteoarthritis
Colour	Yellowing	No early pigment change
Fibrillation	Non-weight-bearing areas, no clefts	Weight-bearing areas with clefts
Eburnation	No	Yes
Water content	Decreased	Increased
Keratan sulfate	Increased	Decreased
Chondroitin 4 to 6 sulfate ratio	Decreased	Increased
Hyaluronate	Increased	Decreased
Proteoglycan aggregation	Normal	Diminished
Proteases	Normal	Increased

• Ageing cartilage accumulates advanced glycation end products, which raise stiffness.
• Early OA cartilage swells, loses proteoglycan by dilution and loosens its collagen network.

Osteoarthritis Histopathology

• Early changes are tidemark duplication and vascular invasion from subchondral bone across the tidemark.
• Collagen orientation changes, chondrocytes increase and proteoglycan synthesis falls.
• Fibrillation and vertical and horizontal clefts follow, with chondrocyte clones (brood capsules) beside them.
• Loss of safranin O or toluidine blue staining reflects glycosaminoglycan loss.
• Horizontal splits may form between calcified and uncalcified cartilage.
• Late disease shows full-thickness loss and eburnation, subchondral cysts, sclerosis and osteophytes.
• Synovitis is mild and patchy, never as marked as in RA.
• Bone scan uptake can precede radiographic OA.

Osteophytes

• Osteophytes form by endochondral ossification at joint margins in nonpressure zones.
• They arise where hyaline cartilage meets synovium or periosteum.
• Their cap is more fibrocartilaginous than articular cartilage.
• Osteophyte chondrocytes express endochondral genes. Articular chondrocytes express BMP and WNT inhibitors that keep them stable.

Numbers to Remember

• Meniscectomy is linked with a 132-fold higher rate of knee replacement than matched peers.
• Ligament injury raises OA risk about tenfold.
• About 12 percent of OA is post-traumatic.
• Rapidly destructive hip OA (Postel) loses 2 mm or half the joint space within a year.
• dGEMRIC works because anionic gadolinium concentrates where negatively charged GAG is depleted.

Source

Vigorita VJ, Ghelman B, Mintz D. Arthritis. In. Vigorita VJ, Ghelman B, Mintz D. Orthopaedic Pathology. 3rd ed. Philadelphia, Wolters Kluwer, 2016.

Mechanosensing, Autophagy and Ageing

• Physiological loading increases aggrecan production. Injurious loading increases degrading enzymes.
• TRPV4 senses physiological loading. Piezo1 and Piezo2 sense injurious forces.
• Autophagy clears damaged components and limits reactive oxygen species.
• Autophagy rises in early osteoarthritis and falls in late disease, promoting apoptosis.
• Senescent chondrocytes show a senescence-associated secretory phenotype (SASP).
• AGEs cross-link collagen and make aged cartilage too stiff.
• Retained G1 fragments bound to hyaluronan block new aggrecan binding and impede repair.

More on ageing biology and genetics

• Superficial zone chondrocytes strongly express autophagy regulators ULK1, Beclin1 and LC3.
• Nine hallmarks of ageing are proposed. Senescence and mitochondrial dysfunction are most linked to primary osteoarthritis.
• COL2, COL9 and COL11 mutations cause chondrodysplasias and early osteoarthritis.
• Asporin polymorphism is linked to knee osteoarthritis. Asporin suppresses TGF-β driven aggrecan and type II collagen.
• Matrilin-3 T298M mutation is linked to hand osteoarthritis.
• A DOT1L variant raises hip osteoarthritis risk, especially in males. DOT1L protects by inhibiting Wnt signalling.
• Acetabular dysplasia, pistol grip deformity and abnormal neck shaft angle may precede hip osteoarthritis by decades.
• The DVWA association in an Asian cohort did not replicate in Europeans.

Numbers to Remember

• Zones. Superficial 10, middle 10, deep 80 percent of depth.
• Half-lives. Type II collagen over 100 years, aggrecan monomer 3.4 years, G1 fragments 25 years.
• Aggregate. Over 200 MDa. Link protein 45 kDa.

Memory Aids

• Six for the nest. Type VI collagen wraps each cell in the chondron.
• TRPV4 for daily, Piezo for damage. Physiological versus injurious load sensors.
• ADAMTS cuts aggrecan first, MMP-13 cuts collagen next. Order of matrix loss.

Exam Traps

• Superficial collagen runs parallel to the surface. Deep collagen runs perpendicular.
• Cell density is highest at the surface and falls with depth.
• Type X collagen appears only in hypertrophic cartilage.
• Aggrecan binds hyaluronan through its G1 domain. G3 lies at the carboxy end.

Related pages. Articular Cartilage Defects of the Knee

Source

Miller RE, Malfait AM. Biology of Articular Cartilage. In. Aaron RK, editor. Orthopaedic Basic Science. Foundations of Clinical Practice. 5th ed. Philadelphia, Wolters Kluwer, 2021.

Practise Type X questions on this topic

Reviewed by Professor Phong Tran, Head of Orthopaedic Surgery, Western Health. Last updated 17 October 2026.