Articular cartilage damage and healing

Articular cartilage damage and healing

• Cartilage is avascular tissue with very limited healing response

• Chondrocyte viability disrupted by:

  • High-impact loads—trauma or lacerations

  • Prolonged excessive stress—obesity, dysplasia, varus/valgus

  • Prolonged lack of stress—inactivity/disuse

  • Chemical issues:

    • Changes in pH: (normally at 7.4)

    • Enzymes—metalloproteases

  • Laceration depth is key factor

    • Lacerations above tidemark demonstrate chondrocyte cloning

      • Limited increases in numbers of chondrocytes

      • Limited repair

    • Lacerations extending below the tidemark into subchondral bone

      • Cause an inflammatory response

      • Marrow mesenchymal stem cells respond and produce less durable fibrocartilage (type I collagen)

    • Forms the basis of the ICRS (International Cartilage Repair Society) grading system

      • Grade 0: normal cartilage

      • Grade 1: nearly normal (superficial lesions)

      • Grade 2: abnormal (lesions extend

        <50% of cartilage depth)

      • Grade 3: severely abnormal (>50% of cartilage depth)

      • Grade 4: severely abnormal (through the subchondral bone)

• Blunt trauma and strenuous loading cause cell apoptosis

  • Effects look similar to those of osteoarthritis

  • Cartilage thinning and proteoglycan loss

• Joint immobilization leads to atrophy or cartilage degeneration

   

   

   

  FIG. 1.29 The layers of articular cartilage and their characteristics and functions. C,

  Cytoplasm; EM, electron micrograph; IF, intermediate filaments; N, nucleus. Composite from Mark R. Brinker MR, Daniel P, O’Connor DP: Basic science. In Miller MD et al, editors: Miller orthopaedic review, Philadelphia, 2012, Saunders, Fig. 1.40; Buckwalter JA, Mankin HJ: Articular cartilage. Part I: tissue design and chondrocyte-matrix interactions, J Bone Joint Surg Am 79:600–611, 1997.

   

  • Continuous passive motion is believed to benefit cartilage healing

  • Four weeks of immobilization decreases proteoglycans/collagen ratio

  • Ratio returns to normal after 8 weeks of joint mobilization

• Joint instability allows abnormal shearing loads

  • Early (≈4 weeks): proteoglycan/collagen ratio is decreased.

  • Late (≈12 weeks): proteoglycan/collagen is elevated and hydration is increased.

  • Instability markedly reduces hyaluronan (disuse does not).

• Beneficial effects of exercise

  • Increased glycosaminoglycans

  • Runners may have increased cartilage thickness

  • Likely due to chondrocyte modulation through mechanotransduction

• Growth factors and cartilage injury

  • IL-1 stimulates MMP, COX-2, and nitric oxide synthetase,

    which degrades cartilage.

  • TGF-β stimulates synthesis of ECM and decreases activity of IL-1 and MMP’s

    • Also stimulates chondrogenesis in vitro

  • BMP-2, BMP-7, and IGF-1 also stimulate ECM production

Changes with aging (see Fig. 1.26)

• Decreased number of chondrocytes (but larger in size)

• Increased lysosomal enzymes

• Senescence markers of chondrocytes include telomere erosion, higher β-galactosidase expression, and reduced Wnt2 expression

• Lower response to growth factors (TGF-β)

  • Decreased matrix production and matrix maintenance

  • Decreased chondroitin SO 4 − (but increased keratan SO 4 − )

• Proteoglycan molecules smaller, so less able to hold water (lower water content)

• Increase in advanced glycosylation end products

  • Yellows and stiffens cartilage

• Greater stiffness or modulus of elasticity but less tensile strength

  • Increased decorin—decorates collagen for cross-links

  • Increased collagen cross-links and diameter

• “Dried up old cartilage is yellow, weak, brittle, & stiff”

Changes with osteoarthritis

• Increase in cells early (cloning)

• Loss of smooth lamina leads to fibrillation/fissures.

  • Higher coefficient of friction

• Chondrocytes react to IL-1β and TNF and produce nitric oxide

• IL-1 stimulates MMPs, which degrade matrix.

  • Collagenases (MMP-13)—first irreversible step

  • Aggrecanase—degrade proteoglycans (ADAMTs)

  • Stromelysin

    • Decreased size and content of proteoglycan molecules

    • Decreased keratan SO4 − and increased chondroitin/keratan ratio

    • Increase in percentage of nonaggregated glycosaminoglycans

    • Higher water content and greater permeability initially followed by lower water content in later stages

• Decreased modulus of elasticity (less stiff) and tensile strength