OPBSPathologyRadiology
Must Know
- OA is a whole joint disease. Damage to bone, synovium or cartilage feeds a destructive loop in the others.
- Subchondral bone changes and synovitis often precede detectable cartilage damage.
- Beneath cartilage lie calcified cartilage, then the subchondral plate, then subchondral trabecular bone.
- No disease modifying OA drug has delayed or prevented OA in humans.
- Radiographic joint space narrowing correlates poorly with pain.
Bone Marrow Lesions
- Also called bone marrow oedema or bone bruise.
- MRI shows ill-defined high signal on fluid sensitive fat saturated sequences and low signal on T1.
- BMLs predict pain and cartilage loss. Growing lesions predict nearby cartilage loss.
- Patients without BMLs lose little cartilage. Shrinking BMLs go with less pain.
- BMLs can appear in asymptomatic people and may precede OA.
- They sit in the overloaded compartment, medial in varus and lateral in valgus knees.
- Whether BMLs cause cartilage loss is unknown.
Subchondral Bone in OA
| Layer | Early OA | Late OA |
|---|---|---|
| Trabecular bone | Faster remodelling, less mineral, net bone loss, more deformable | Both higher and lower volume reported |
| Subchondral plate | Thins, porosity rises | Thickens, most where joint space narrows |
| Calcified cartilage | Not stated | Advances into uncalcified cartilage, tidemark duplication |
- Trabecular plates add more joint stiffness than rods. The plate to rod ratio shifts in OA.
- OA subchondral bone shows reduced perfusion and venous stasis, causing hypoxia.
- Thick plate plus expanded calcified cartilage forms subchondral sclerosis.
- Calcified cartilage converts cartilage shear into compressive and tensile force.
- Mineralised plate protrusions into cartilage occur in OA and alkaptonuria, concentrating stress.
- Osteophytes form by endochondral ossification of periosteal or synovial stem cells.
- Osteophytes appear on radiographs before joint space narrowing. Size does not predict progression.
- About half of cartilage glucose and oxygen comes from subchondral vessels, the rest from synovial fluid.
- Late OA brings vessel and nerve invasion into calcified cartilage, sometimes to the tidemark.
- Osteocyte perilacunar canalicular remodelling (PLR) is impaired in OA and osteonecrosis.
More on animal models and porosity
- Dunkin-Hartley guinea pigs develop OA after 3 months, with plate to rod ratio rising at 2 months.
- Strain 13 guinea pigs have high bone mass without OA, so bone mass alone is not causal.
- A metal rod stiffening sheep subchondral bone caused no cartilage damage after five years.
- Antiresorptives given before OA induction in animals reduce cartilage damage.
- Widened plate channels raise transport of molecules up to 70 kDa by 30 to 100 percent.
- Microcracks open new solute paths. Diffusion between chondrocytes and osteocytes slows in mouse OA.
- Osteocytes perform PLR by secreting proteases and acid. Suppressing PLR causes joint disease in mice.
- Hand OA occurs twice as often in women.
- Removing osteophytes destabilises the joint, hinting they form to stabilise it.
- BMLs seen on both T1 and fluid sensitive sequences may be more severe.
Synovium in OA
- Healthy synovium stops capsule adhering to cartilage, makes fluid, hyaluronan and lubricin, and clears debris.
- It is vascular and carries nociceptive fibres.
- The intima holds type A macrophage like and type B secretory fibroblast synoviocytes.
- IL-1β and TNF-α are the most prominent OA cytokines.
- Other mediators are nitric oxide, PGE2, neuropeptides and VEGF.
- Synovial macrophages can become osteoclasts and erode subchondral bone.
- Cartilage breakdown products released into the joint induce synovitis.
- Contrast MRI shows synovial thickening. Noncontrast MRI underestimates synovitis.
- Synovitis independently predicts incident OA. MRI cartilage damage did not predict radiographic OA at 2 years.
Biological Cross-talk
| Pathway | Healthy role | OA change |
|---|---|---|
| HIF-1α | Protects hypoxic chondrocytes from apoptosis | Falls with more oxygen from vascular invasion |
| HIF-2α | Not stated | High in OA cartilage, induces aggrecanases and MMPs |
| Wnt and β-catenin | Drives bone formation, ossification centres and chondrocyte survival | Overactive in OA synovial fibroblasts and chondrocytes |
| Sclerostin | Mechanosensitive Wnt brake from osteocytes and chondrocytes | Overload lowers it, causing sclerosis |
| TGF-β in bone | Released by osteoclasts, recruits osteoprogenitors, blocks terminal mineralisation | High in subchondral bone, linked to cartilage loss |
| TGF-β in cartilage | Raises type II collagen and aggrecan, restrains MMP-13 | Blocking it worsens OA. Smad3 mutations link to OA |
- MMP-13 maintains bone canaliculi yet is the main protease cleaving type II collagen.
- Sclerotic bone osteoblasts secrete IL-6, IL-8 and PGE2, inducing chondrocyte MMP-13.
- Normoxic chondrocytes make less type II collagen and aggrecan and more MMP-13 and MMP-3.
| Marker | Fragment of | Cleaved by |
|---|---|---|
| CTX-II | Type II collagen | Proteases |
| ARGS | Aggrecan | Aggrecanase |
| NTX-I | Type I collagen | Cathepsin K |
More on hypoxia and cell studies
- Chondrocytes cocultured with bone resist apoptosis even when physically separated.
- HIF-1 inhibition in mice promotes cartilage loss and osteophytes.
- Hypoxic osteoblasts make more TGF-β1, IGF-1 and type I collagen and die more easily.
- Neutralising TGF-β antibody preserved cartilage and bone in a mouse OA model.
- Matrix fragments such as fibronectin and small leucine rich proteoglycans activate integrins.
- Diagnostic value of fragment markers is unclear.
Mechanical Cross-talk
- Low intensity cyclic loading raises aggrecan, suppresses proteases and blunts cytokine catabolism.
- Passive motion raises hyaluronan secretion.
- Immobilisation causes OA in rodents. Injurious load raises MMP-13, IL-1β, NOS and prostaglandins.
- Integrins form focal adhesions. Protective load effects need integrins and are lost in OA.
- TRPV4 is a mechanosensitive calcium permeable cation channel on primary cilia, triggered by osmotic swings.
- TRPV4 suppresses catabolism and induces Col2a1. Its loss causes fibrillation and proteoglycan loss.
- A stiff subchondral plate stress shields trabecular bone, prompting resorption.
Therapy Trials
| Agent | Finding |
|---|---|
| Diphosphonates | Meta-analysis shows no benefit over placebo, no extra harm |
| Zoledronic acid infusion | Less pain and BML area at 6 months only |
| Oral calcitonin | Same as placebo, no effect on joint space narrowing |
| Strontium ranelate | Over 3 years limited narrowing, improved pain, shrank BMLs |
| Intra-articular triamcinolone 12 weekly for 2 years | No pain benefit and more cartilage loss |
| Chondroitin sulfate | Less BML area and cartilage loss, no pain change |
| Celecoxib | Small pain gain, lost in high quality trials |
| Tanezumab (anti-NGF) | Less pain, better function. With NSAIDs, more rapidly progressive OA |
| Microfracture | Fibrocartilage, cysts, bone overgrowth, plate fragility, no long term benefit |
Numbers to Remember
- Channel sizes. Vessel and nerve channels 10 to 30 µm, marrow pores 30 to 100 µm, canaliculi 500 nm.
- Bone to cartilage pathways. 5 to 50 nm.
- Compliance. A 10 percent fall raises cartilage compressive stress 15 to 20 percent.
- Injury. Post injury OA appears nearly 30 years before age related OA.
- ACL rupture. About 50 percent of footballers show narrowing and osteophytes at 12 years, whatever the treatment.
Memory Aids
- One good, two bad. HIF-1α protects chondrocytes. HIF-2α drives catabolism.
- Thin then thick. Subchondral plate thins early and thickens late.
Exam Traps
- BMLs are low signal on T1 and high signal on fat saturated fluid sequences.
- TGF-β inhibition helps subchondral bone but harms cartilage.
- Sustained intra-articular steroid worsens cartilage loss.
- Sclerostin comes from chondrocytes as well as osteocytes.
Source
Mazur CM, Bailey KN, Alliston T. Joint Cross-talk Among Bone, Synovium, and 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.