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📚 Pathology Class Test Notes

Monday, 27th July | Musculoskeletal Pathology

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MS-Pa-001 | Muscle Remodeling

Learning Objective: Hyperplasia, Hypertrophy, and Atrophy of Muscle Fibre

🔴 Muscle Hypertrophy

• Occurs in response to increased work demand (e.g., exercise, chronic loading)
• The myofibrils within each fibre increase in number and size
• New sarcomeres are added at the ends of muscle fibres when a muscle is stretched to greater than normal length - new sarcomeres can be added at a rate of several per minute
• Enzyme systems for energy production also increase, especially glycolytic enzymes, to supply rapid energy during forceful contraction

• Satellite cells - adult stem cells that lie quiescent beneath the basal lamina above the sarcolemma
• Upon activation (by exercise or injury), they proliferate, differentiate, migrate through the sarcolemma, and fuse with existing fibres to contribute to repair and hypertrophy
• Some satellite cells self-renew to ensure continued repair capacity

Satellite cells: quiescent beneath basal lamina → activated → proliferate → differentiate → fuse with fibre or self-renew (Guyton & Hall, Medical Physiology)

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🔴 Muscle Hyperplasia

• Occurs only under extreme conditions of muscle force generation
• Increase is only by a few percent - a minor contributor compared to hypertrophy
• Primary mechanism: Linear splitting of previously enlarged fibres (not satellite cell division producing new fibres)
• Occurs in addition to fibre hypertrophy, not instead of it

Source: Guyton & Hall Textbook of Medical Physiology

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🔴 Muscle Atrophy

1. Disuse Atrophy

• When a muscle remains unused for many weeks, the rate of degradation of contractile proteins exceeds replacement
• The key pathway: ATP-dependent Ubiquitin-Proteasome Pathway
  • Proteasomes = large protein complexes that degrade damaged or unneeded proteins by proteolysis
  • Ubiquitin = regulatory protein that labels cells targeted for proteosomal degradation
• Conversely: when a muscle remains shortened to less than normal length, sarcomeres at the ends disappear

2. Denervation Atrophy

• When a muscle loses its nerve supply, it no longer receives signals to maintain normal size
• Atrophy begins almost immediately after denervation
• After ~2 months: degenerative changes appear in fibres
• If nerve regrows rapidly: full return of function possible in as little as 3 months
• No further functional return after 1-2 years of denervation

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MS-Pa-003 | Diseases of Bone

Learning Objective 1: Osteoporosis - Clinical Presentation & Histological Justification

Definition

• Radiographically: bone mass ≥ 2.5 SD below mean peak bone mass in young adults (T-score ≤ -2.5)
• Osteopenia = 1 to 2.5 SD below the mean

Types

Pathogenesis

1. Reduced estrogen (postmenopausal) - estrogen normally suppresses RANKL and promotes OPG (decoy receptor); its loss → unchecked osteoclast activity
2. Age-related changes - osteoblasts have reduced biosynthetic response to growth factors
3. Reduced physical activity - osteocytes detect mechanical stress and signal bone formation; reduced activity reduces this stimulus
4. Calcium/Vitamin D deficiency - impairs mineralization and increases PTH

• RANKL (on osteoblasts/stromal cells) binds RANK on osteoclast precursors → osteoclast differentiation and bone resorption
• OPG (osteoprotegerin) = decoy receptor secreted by osteoblasts in response to WNT signaling → blocks RANKL-RANK binding → inhibits resorption
• Estrogen loss tips the balance toward RANKL dominance

Paracrine regulation of osteoclast formation via RANKL/RANK/OPG (Robbins Basic Pathology)

Histological Features (Justification)

• Bone that is present is normally mineralized (this distinguishes it from osteomalacia)

• Trabecular plates become thinned and perforated
• Loss of interconnections between trabeculae
• Leads to microfractures → eventually vertebral body collapse
• Characteristic: loss of horizontal trabeculae with relative preservation of vertical trabeculae

• Cortex is thinned by subperiosteal and endosteal resorption
• Haversian systems are widened

(A) Osteoporotic vertebral body - loss of horizontal trabeculae, compression fractures. (B) Advanced osteoporosis - thinning of both trabecular and cortical bone (Robbins Pathologic Basis of Disease 10e)

Clinical Features

• Vertebral fractures (thoracic & lumbar) - painful; multiple fractures → loss of height, kyphoscoliosis, lumbar lordosis
• Femoral neck, pelvis, spine fractures → immobilization → pulmonary embolism, pneumonia → >50,000 deaths/year
• Plain X-rays: osteoporosis NOT detectable until 30-40% of bone mass is lost
• Blood tests (Ca, PO4, Alk Phos) are usually normal
• Diagnosis: DEXA scan (dual-energy X-ray absorptiometry) or quantitative CT

Treatment

• Exercise, calcium & Vitamin D supplementation
• Bisphosphonates - reduce bone resorption (first-line)
• Denosumab - anti-RANKL antibody (promising for postmenopausal osteoporosis)
• Menopausal hormone therapy (estrogen) - slows bone loss but limited by DVT/stroke risks

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Learning Objective 2: Osteopetrosis - Clinical Presentation & Histological Justification

Definition

• Reduced bone resorption due to impaired osteoclast formation or function
• Diffuse, symmetric skeletal sclerosis
• Bones appear stone-like on X-ray but are abnormally brittle and fracture easily

Pathogenesis

Classification

Histological Features

• Bones are hyperdense and sclerotic - medullary canal is obliterated by unresorbed bone
• Osteoclasts may be increased in number but are non-functional (resorption pits absent)
• Woven bone persists - normal remodeling to lamellar bone does not occur
• Cartilage remnants within bone (in growth plate region) - endochondral ossification occurs but chondroclasts cannot resorb the primary spongiosa
• On X-ray: characteristic "Erlenmeyer flask" deformity of metaphyses; "bone within bone" appearance

Clinical Features

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Learning Objective 3: Steps of Bone Repair (Briefly)

Three Stages of Fracture Repair

Stage 1: INFLAMMATION (Days 1-7)

1. Fracture disrupts periosteum and blood vessels → Fracture hematoma forms
2. Hematoma provides hematopoietic cells that secrete growth factors (TGF-β, PDGF, BMP)
3. Neutrophils and monocytes arrive → phagocytosis of debris
4. Fibroblasts, mesenchymal cells, and osteoprogenitor cells migrate to site
5. Granulation tissue forms around fracture ends

Stage 2: REPAIR (Weeks 2-12)

1. Primary callus response within 2 weeks
2. For fracture ends not in continuity: soft (bridging) callus forms - consists of fibrocartilage and fibrous tissue (type II collagen expressed early)
3. Soft callus undergoes endochondral ossification → replaced by woven bone (hard callus)
4. Intramedullary (medullary) callus forms more slowly to supplement bridging callus
5. Amount of callus is inversely proportional to degree of immobilization (more motion = more callus)
6. Type II collagen (cartilage) → Type I collagen (bone) transition

Stage 3: REMODELING (Months to years - up to 7 years)

1. Begins in the middle of the repair phase
2. Woven bone is replaced by lamellar bone (organized parallel collagen)
3. Bone remodels according to Wolff's Law - assumes normal configuration according to mechanical stress and electric charges (piezoelectric)
4. Fracture healing is complete when the marrow space is repopulated
5. Extramedullary callus provides greater structural strength than intramedullary callus (bending stiffness increases with the 4th power as callus is deposited further from the neutral axis)

Source: Miller's Review of Orthopaedics 9e; Rockwood & Green's Fractures in Adults 10e

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MS-Pa-004 | Disease of Cartilage

Learning Objective: Histological Basis for Bone Repair After Fracture AND Cartilage Growth and Repair

Part A: Histological Basis of Bone Repair

1. Hematoma - clot provides scaffold and growth factor reservoir (TGF-β, BMP, PDGF)
2. Fibrovascular granulation tissue - fibroblasts synthesize collagen type III initially
3. Soft callus (fibrocartilage) - chondrocytes differentiate from MSCs; type II collagen deposited; resembles growth plate
4. Hard callus (woven bone) - endochondral ossification converts fibrocartilage to woven bone via osteoblast activity; type I collagen replaces type II
5. Remodeling to lamellar bone - osteoclasts resorb woven bone; osteoblasts deposit organized lamellar bone along stress lines

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Part B: Cartilage Growth and Repair

Normal Cartilage Growth

1. Appositional growth - new cartilage added at the periphery by chondroblasts from the perichondrium, which differentiate into chondrocytes
2. Interstitial growth - chondrocytes within lacunae divide and produce new matrix from within (possible because cartilage matrix is flexible) - this is the main mechanism of long bone elongation at growth plates

Cartilage Repair - Why It Fails

1. Avascular - no blood supply to initiate or support repair
2. Low cell density - few chondrocytes per unit volume
3. Low migratory capacity - chondrocytes do not migrate readily through the dense matrix to the injury site
4. Limited stem cell population - insufficient progenitors to repopulate defects
5. Chondrocyte death in tissue surrounding the injury impairs integration

Response to Isolated Chondral Injury (No subchondral bone involvement)

• Viable chondrocytes near injury may proliferate and form clusters (chondrocyte clones)
• Synthesize new matrix - but insufficient to recapitulate native cartilage
• Synovial mesenchymal progenitor cells may migrate to defect via:
  • Direct contact with synovium, or
  • Pannus-like migration of synovial membrane onto articular surface
• These progenitors (marked by DPP4 and PI16 expression; derived from GDF-5-expressing joint interzone lineage) can differentiate into chondrocyte-like cells and deposit repair matrix
• Mediated in part by YAP1 (Yes-associated protein-1)
• Result: Functionally inferior fibrocartilage - not true hyaline cartilage

Response to Osteochondral Injury (Subchondral bone also involved)

1. Subchondral vessels rupture → hematoma fills both bony and chondral defect
2. Inflammatory phase: neutrophils/monocytes → phagocytosis of debris
3. Mesenchymal progenitors from bone marrow migrate into clot → synthesize collagenous matrix
4. Some cells assume rounded morphology → synthesize type III and type I collagen (not native type II + proteoglycans)
5. Within weeks: differentiation into fibrocartilaginous and osseous tissues → fibrocartilage repair tissue
6. The repair matrix has some chondrocyte-like properties but is type I/III collagen-rich rather than type II collagen + proteoglycans (as in native hyaline cartilage)
7. Subsequent fate varies - some defects improve, others deteriorate

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📝 Quick Revision Summary Table

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