Related anatomy and physiology
The normal joint
●A joint can be defined as a place where two or more bones meet.
●There are three types of joints: fibrous, fibrocartilaginous and synovial.
Fibrous and fibrocartilaginous joints
●These include the intervertebral discs, the sacroiliac joints, the pubic symphysis and the costochondral joints.
●Skull sutures are fibrous joints. Little movement occurs at such joints.
Synovial joints
●Synovial joints include the ball-and-socket joints (e.g. hip) and the hinge joints (e.g. interphalangeal).
●They are designed to allow movement, which is restricted to a required range, and stability is maintained during use.
●The load is distributed across the surface, thus preventing damage by overloading or disuse.
●Each structural component of a synovial joint plays a key functional role, and different components are affected in different disease processes.
Juxta-articular bone
●The bone that abuts a joint (juxta-articular bone) is highly vascular and comprises a light framework of mineralized collagen enclosed in a thin coating of tougher, cortical bone.
●It withstands pressure poorly if the normal intra-articular covering of hyaline cartilage is worn away, as in osteoarthritis.
●This process can lead to abnormalities of bone growth and remodelling
Articular cartilage
●The hyaline cartilage lining the bones within a joint is called articular cartilage.
●It is avascular and derives nourishment from synovial fluid. It is predominantly composed of type II collagen, encoded by the COL2A1 gene, which forms a mesh-like network.
●Within the mesh are giant macromolecular aggregates of proteoglycan.
●These heterogeneous macromolecules comprise protein chains with side-chains of the carbohydrates keratan and chondroitin sulphate(aggrecans).
●These molecules have a negative charge and retain water in the structure by producing a dynamic tension between the retaining force of the collagen matrix and the expansive effect of osmotic pressure. Articular cartilage cont…
●Intermittent pressure from ‘loading’ of the joint is essential to normal cartilage function and encourages movement of water, minerals and nutrients between cartilage and synovial fluid.
●Chondrocytes secrete collagen and proteoglycans, and are embedded in the cartilage.
●They migrate towards the joint surface along with the matrix they produce.
●Defects in articular cartilage and underlying bone are features of osteoarthritis.
Synovium and synovial fluid
●The joint capsule, which is connected to the periosteum, is lined with synovium, which is a few cells thick and vascular.
●Its surface is smooth and non-adherent, and is permeable to proteins and crystalloids.
●As there are no macroscopic gaps, it is able to retain normal joint fluid, even under pressure.
●Macrophages and fibroblast-like synoviocytes form the synovial layer by cell-to-cell interactions mediated by cadherin II.
●The synoviocytes release hyaluronan into the joint space, which helps to retain fluid in the joint.
●Synovial fluid is a highly viscous fluid secreted by the synovial cells and has a similar consistency to plasma.
●Glycoproteins ensure a low coefficient of friction between the cartilaginous surfaces.
●Tendon sheaths and bursae are also lined by synovium.
●Inflammation of the synovium is a feature of inflammatory arthritis.
Ligaments and tendons
●These structures stabilize joints.
●Ligaments are variably elastic and this contributes to the stiffness or laxity of joints.
●Tendons are inelastic and transmit muscle power to bones.
●The joint capsule is formed by intermeshing tendons and ligaments.
●The point where a tendon or ligament joins a bone is called an enthesis and may be the site of inflammation.
●Whereas most ligaments and tendons run outside the joints, some, like the supraspinatus tendon in the shoulder and the cruciate ligaments in the knee, run through the joint.
●Inflammation or trauma to these joints can cause severe joint symptoms.
Blood vessels and nerves
●The ligaments, periosteum, synovial tissue and capsule of the joint are richly supplied by blood vessels and nerves.
●Pain usually derives from inflammation of these sites because the synovial membrane is relatively insensitive.
Enzymes and cytokines
●Connective tissue constantly undergoes repair and remodelling.
●Degradation is mediated by enzymes such as aggrecanase and matrix metalloproteinases (MMPs), which require zinc and act at a neutral pH.
●There are several MMPs that act on different collagens, such as the gelatinases (MMP-2 and 9), which degrade denatured collagen.
●MMPs also act on non-collagen proteins: for example, the stromelysins (MMP-3, 10 and 11), which degrade proteoglycans and fibronectin.
●The turnover of normal collagen is initiated by cytokines: for example, interleukin-1 (IL-1) synthesized by chondrocytes.
●Activation of latent MMPs and tissue plasminogen activator then occurs.
●Two inhibitors, TIMP (tissue inhibitor of metalloproteinase) and plasminogen activator inhibitor-1 (PAI-1), inhibit degradation during matrix remodelling.
Skeletal muscle
●This tissue consists of bundles of myocytes containing actin and myosin molecules.
●These molecules interdigitate and form myofibrils, which cause muscle contraction in a similar way to myocardial muscle.
●Bundles of myofibrils (fasciculi) are covered by connective tissue, the perimysium, which merges with the epimysium (covering the muscle) and forms the tendon, which attaches to the bone surface (enthesis).
●Though not strictly a component of the joint itself, muscles are so closely related to joints that strain and tension in muscles are commonly interpreted by patients as joint pain.
●Pain in muscles and ligaments (myofascial pain) is a very common cause of locomotor symptoms.
●Primary inflammatory disease of muscle (myositis) is far less common.
Bone
Bone is a specialized connective tissue serving three major functions:
●Mechanical – supplying structure and muscle attachment for movement
●Metabolic – providing the body's primary store of calcium and phosphate
●Protective – enclosing the marrow and other vital organs.
Bone structure
●Bone is comprised of cells and a matrix of organic protein and inorganic mineral.
●Long bones (femur, tibia, humerus) and flat bones (skull, scapula) have different embryological templates, with varying proportions of cortical and trabecular bone.
●Cortical (compact or lamellar) bone forms the shaft of long bones and the outer shell of flat bones. Formed of concentric rings of bone, it is particularly adapted to withstand bending strain.
●Trabecular (cancellous) bone is found at the ends of long bones and inside flat bones. Comprised of a network of interconnecting rods and plates of bone, it offers resistance to compressive loads. It is also the main site of bone turnover for mineral homeostasis.
●Woven bone lacks an organized structure. It appears in the first few years of life, at sites of fracture repair and in high-turnover bone disorders such as Paget's disease.
Matrix components
●Type I collagen is the main protein, forming parallel lamellae of differing density (which impairs spreading of cracks). In cortical bone, concentric lamellae form around a central blood supply (Haversian system), which communicates via transverse (Volkmann's) canals.
●Non-collagen proteins include osteopontin, osteocalcin and fibronectin.
●Bone mineral largely consists of calcium and phosphate in the form of hydroxyapatite.
Bone cells
Osteoblasts
●Derived from local mesenchymal stem cells, these cells synthesize matrix (osteoid) and regulate its mineralization.
●After bone formation, the majority of osteoblasts are removed by apoptosis, others remaining at the bone/marrow interface as lining cells or within the bone as osteocytes.
●Osteoblasts regulate bone resorption through the balance in expression of the stimulatory receptor activator of nuclear factor kappa B ligand (RANKL) and its antagonist, osteoprotegerin (OPG).
●Osteoblasts are rich in alkaline phosphatase and express receptors for parathyroid hormone (PTH), oestrogen, glucocorticoids, vitamin D, inflammatory cytokines and the transforming growth factor-beta (TGF-β) family, all of which may therefore influence bone remodelling.
Osteocytes
●These small cells, derived from osteoblasts, are embedded in bone and interconnected with each other and with bone lining cells through cytoplasmic processes.
●They respond to mechanical strain by undergoing apoptosis or through altered cell signalling, which in turn activates bone formation with or without prior resorption.
●As osteocytes also express RANKL and OPG, the relative importance of osteocytes and osteoblasts in bone resorption function continues to be explored.
Osteoclasts
●These cells have the unique capacity to resorb bone and are derived from haemopoietic precursors of the macrophage lineage.
●In response to RANKL, macrophage colony stimulating factor (M-CSF) and local adhesion factors (integrins), osteoclasts attach to bone, creating a ruffled border that forms a number of extracellular lysosomal compartments.
●Hydrogen ions are actively secreted into these spaces and the acid environment removes the mineral phase before specialized cysteine proteases (e.g. cathepsin K) resorb the collagen matrix.
Bone growth and remodelling
●Longitudinal growth occurs at the epiphyseal growth plate, a cartilage structure between the epiphysis and metaphysis
●Cartilage production is tightly regulated, with subsequent mineralization and growth finally arrested at 18–21 years, when the epiphysis and metaphysis fuse.
●In adults, bone is regularly remodelled to ensure repair of microdamage and turnover of calcium and phosphate for homeostasis.
●This remodelling cycle is carried out by the basic multicellular unit (BMU).
●Signals initiating resorption include osteocyte apoptosis and altered signalling (sclerostin, prostaglandins, RANKL and other molecules), resulting in localized retraction of bone-lining cells and binding of multinucleate osteoclasts to the bone surface, followed by bone resorption.
●Bone formation involves reciprocal effects of wnt versus dickkopf (Dkk) and sclerostin on the LRP5/6-β-catenin pathway.
●The switch from resorption to formation may rely on osteocyte signalling or on release of signals from the bone matrix, such as TGF-β.
●Bone remodelling is said to be coupled when formation follows resorption, but may be unbalanced when the amount of bone removed is not replaced with an equal amount.
Examples of bone remodelling include:
●Myeloma cells have dual lytic effects, with enhanced expression of RANKLand expression of Dkk
●In rheumatioid arthritis, RANKLand Dkk are increased
●In spondyloarthritis (characterized by new bone formation alongside erosion) Dkk is inhibited, with the increased wnt activity also increasing OPG relative to RANKL
●Corticosteroids may increase osteocyte SOST expression, and stimulate expression of Dkk.
Calcium homeostasis and its regulation
●Calcium homeostasis is regulated by the effects of PTH and 1,25-dihydroxyvitamin D (1,25(OH)2D3) on gut, kidney and bone.
●Calcium-sensing receptors are present in the parathyroid glands, kidney and brain.
Calcium absorption and distribution
●Daily calcium consumption, primarily from dairy foods, is 20–25 mmol (800–1000 mg).
●The combined effect of calcium and vitamin D deficiency contributes to the bone fragility seen in some older persons.
●Intestinal absorption of calcium is reduced by vitamin D deficiency and in malabsorption states
Vitamin D metabolism
●The primary source of vitamin D in humans is photoactivation in the skin of 7-dehydrocholesterol to cholecalciferol, which is then converted first in the liver to 25-hydroxyvitamin D (25(OH)D3) and subsequently in the kidney (by the enzyme 1α-hydroxylase) to 1,25(OH)2D3.
●This step can occur in lymphomatous and sarcoid tissue, resulting in hypercalcaemia
●Regulation of the latter step is by PTH, phosphate and feedback inhibition by 1,25(OH)2D3
Parathyroid hormone
●PTH increases renal phosphate excretion and increases plasma calcium by:
- Increasing osteoclastic activity in bone (a rapid response)
- Increasing intestinal absorption of calcium (a slower response)
- Increasing 1α-hydroxylation of vitamin D (the rate-limiting step)
- Increasing renal tubular reabsorption of calcium.
●Hypomagnesaemia can suppress the normal PTH response to hypocalcaemia.
Calcitonin
●Calcitonin is produced by thyroid C cells.
●Although calcitonin inhibits osteoclastic bone resorption and increases the renal excretion of calcium and phosphate, neither excess calcitonin (seen in medullary carcinoma of the thyroid) nor its deficiency following thyroidectomy has significant skeletal effects in humans.
vRelated Pathology
Pathology of osteomyelitis
1.Inflammation if treated there is remodelling of the bone and resolution
2.Suppuration. of process
3.Necrosis
4.New bone formation
5.Resolution
Septic arthritis
Osteopenia
Osteoporosis
A generalised bone disease characterised
●By a decreased bone mass
●Deterioration of bone microarchitecture
●With a resultant increase in fracture risk
Rheumatoid arthritis
SLE
Sjögren syndrome
Antiphospholipid syndrome
Osteoarthritis
●Cartilage is smooth surfaced and shock-absorbing. Under normal circumstances, there is dynamic balance between cartilage destruction by wear and its production by chondrocytes
●Early in development of osteoarthritis, this balance is lost and despite increased synthesis of extracellular matrix, the cartilage becomes oedematous, focal erosion of cartilage develops, chondrocytes die.
●Eventually ECM synthesis fails and surface becomes fibrillated and fissured
●Cartilage ulceration exposes underlying bone to increased stress, producing micro fractures and cysts
●Bone attempts repair but produces abnormal sclerotic subchondral bone and overgrowths at joint margins,
osteophytes
Spondylarthritis
Reactive arthritis
Psoriatic arthritis
Disc generation
Soft tissue rheumatism
Myopathies
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Osteomalacia can present as proximal myscle weakness => waddling gate
Precaution with corticosteroid
Prednisolone tablet size is 5mg but side effect of osteoporosis isnt dose dependant. Even 2.5 mg can cause A/E in bone even in the very short term. So if given for months long, always take precuations llike vit D and cal and alendronate and phosphate binders!
2 erpm class and complications