OPBSMusculoskeletalPharmacology
Must Know
- Extracellular matrix acts as structural scaffold, growth factor store and a channel for cell communication.
- Cartilage matrix turns over very slowly. Articular chondrocytes rarely divide, so cartilage grows by matrix deposition.
- Bone matrix remodels almost continually, repairing microdamage that would otherwise lead to fracture.
- Osteocytes make sclerostin, a Wnt inhibitor that suppresses bone formation.
- Anabolic stimuli activate Wnt, lower osteocyte sclerostin and switch on osteoblasts.
- Type I collagen is a heterotrimer of two α1(I) and one α2(I) chains, giving tensile strength.
- Type II collagen is a homotrimer of three α1(II) chains.
- In osteogenesis imperfecta the chapter describes homotrimeric type I collagen that kinks and cross-links poorly.
- Proteoglycans absorb and release water, so matrix resists compression.
- Chondroitin sulphate, a sulphated glycosaminoglycan, gives cartilage compressive resistance.
Bone Versus Cartilage Matrix
| Feature | Bone | Cartilage |
|---|---|---|
| Main collagen | Type I heterotrimer | Type II homotrimer (with type IX in hyaline) |
| Water | About 30 percent | About 80 percent |
| Proteoglycan | Under 1 percent | About 15 percent |
| Turnover | Near continual remodelling | Very slow |
| Made by | Osteoblasts | Chondroblasts |
- COL2A1 mutations cause collagenopathies such as Stickler syndrome and OA with mild chondrodysplasia.
- Aggrecan breakdown lowers cartilage load-bearing capacity and can progress to OA.
- Mutations in type II collagen, COMP and matrilins are associated with OA.
More on collagen mutations
- COL2A1 disorders listed also include achondrogenesis type II and Legg-Calvé-Perthes disease.
- Mutation types include point, missense, deletion, insertion, frameshift and complex rearrangements, probably causing helical instability and misfolding.
- Homotrimeric type I collagen also occurs in fetal tissue, fibrosis and cancer.
Matrix as a Store
- The skeleton holds 99 percent of body calcium, stored as hydroxyapatite.
- Falling blood calcium triggers PTH, which releases calcium from bone.
- PTH raises renal calcium reabsorption directly and boosts vitamin D activity indirectly.
- Calcitonin from thyroid parafollicular cells opposes PTH and reduces osteoclast activity.
- FGFs, VEGFs, TGFs, BMPs and Wnts bind heparan sulphate on matrix proteoglycans.
- Matrix metalloproteinases release bound growth factors.
Patterning and Lineage
- Hox genes give mesoderm-derived skeletal cells a positional code, in axial and limb skeletons.
- Neural crest derived head and face skeleton lacks Hox expression and shows high plasticity.
- Periosteal progenitors express Hox genes, which help keep them multipotent.
- High Sox9 with low Runx2 gives cartilage. High Runx2 with low Sox9 gives bone.
- Runx2 (Cbfa1) drives type I collagen and osteocalcin and is needed for bone and cartilage.
- Stem cells on soft substrate become neuronal. On stiff, bone-like substrate they become osteoblasts.
- Integrins span the membrane linking cytoskeleton to matrix and are the likely stiffness sensors.
More on evolution and mechanics
- Moving onto land about 400 million years ago made the skeleton lighter and more flexible.
- Hollow bones are lighter and stronger in bending than solid bones of the same diameter.
- Trabeculae remodel along lines of tension and compression.
- Integrins can switch to a high affinity state under force, though the transduction mechanism is unclear.
Cortical and Cancellous Bone
- Cortical bone has dense concentric lamellae, with fibrils in neighbouring lamellae at right angles.
- Cancellous bone has a looser, porous matrix.
| Bone type (clinical scheme) | Description | Biology |
|---|---|---|
| Type I | Least vascular, most homogeneous | Few dividing cells, little collagen laid down, high strain, fibrous healing |
| Type II | Cortex with marrow cavity | Not described |
| Type III | Mainly trabecular | More periosteal proliferation, more Wnt progenitors, faster healing |
| Type IV | Very thin cortex, low density trabeculae | Not described |
- Early mineral stiffens the repair site, lowers strain and favours bone, a positive feedback loop.
Cartilage Types
| Type | Sites | Collagen | Healing |
|---|---|---|---|
| Hyaline | Most joint surfaces | II and IX | Does not regenerate |
| Fibrocartilage | Costal cartilage, nose, larynx, trachea, disc, menisci, TFCC | I and II, proportions vary | Limited. Meniscal red zone heals, white zone does not |
| Elastic | Ear | Elastic fibre bundles | Not described |
- Meniscus has more type I than type II collagen. Anulus fibrosus has roughly equal amounts.
- Osteophytic fibrocartilage has no type I collagen.
- Fibrocartilage has layered parallel collagen bundles in alternating directions, giving moderate elasticity.
- In damaged hyaline cartilage chondrocytes are the only cells, so they both degrade and rebuild matrix.
| Hyaline zone | Feature |
|---|---|
| Superficial | Thinnest, touches synovial fluid |
| Transitional | Random collagen fibres, more proteoglycan than superficial |
| Radial | Lower cell density, nourished by diffusion |
| Calcified | Deepest, on subchondral bone, makes type X collagen, metabolically active |
- Growth plate order runs resting, proliferating (columns), prehypertrophic, then hypertrophic in calcified matrix.
- Proliferating chondrocytes supply the cells for longitudinal growth.
- Hypertrophic chondrocytes can transdifferentiate into osteoblasts.
Ageing and Drugs
- Same BMD can carry different fracture risk in young and old.
- Rising fracture risk with age reflects declining remodelling and microdamage repair.
- Bisphosphonates and RANKL inhibitors build bone but allow microdamage to accumulate.
- Atypical femoral fractures on bisphosphonates carry high relative but low absolute risk.
- Denosumab is a human monoclonal antibody to RANKL, blocking osteoclast formation, function and survival.
- Teriparatide, hPTH(1-34), is anabolic and promotes bone formation.
- Romosozumab is an anti-sclerostin antibody that raises Wnt signalling and bone formation.
- Wnt signalling declines with age.
Stem Cell Niches
- Haematopoietic stem cells sit beside endosteal osteoblasts or endothelial cells.
- Marrow skeletal stem cells form cartilage and bone by an endochondral-like route.
- Periosteal stem cells form bone by intramembranous ossification and can make cartilage after injury.
- Osteopetrosis and osteoporosis appear to shrink the skeletal stem cell pool.
Numbers to Remember
- Body calcium in skeleton. 99 percent.
- Yearly renewal in adults. Trabecular bone 25 percent, cortical bone about 2 to 3 percent.
- Atypical femoral fracture on bisphosphonates. 3.2 to 50 per 100,000 person-years.
- Teriparatide. First 34 amino acids of human PTH.
Memory Aids
- Hox for mesoderm, none for neural crest. No Hox, more plasticity.
- Sox up, cartilage. Runx up, bone. The ratio picks the fate.
- Red heals, white does not. Vascular outer meniscus against avascular inner meniscus.
Exam Traps
- Meniscus is fibrocartilage with more type I than type II collagen.
- Calcified zone chondrocytes are metabolically active.
- Hypertrophy is not always terminal. Hypertrophic chondrocytes can become osteoblasts.
- Teriparatide builds bone. Bisphosphonates and denosumab block resorption.
- Calcitonin lowers osteoclast activity, opposing PTH.
Related pages. Bone as a biomaterial
Source
Li Z, Helms J. Biology and Mechanics of the Skeletal Extracellular Matrix. 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.