The musculoskeletal system is comprised of bones and connective tissue structures, such as cartilage, ligaments, and tendons. These structures are brought into motion by skeletal muscles. To withstand resultant forces, bone tissue resists pressure and tension and is minimally elastic. Bone tissue mainly consists of bone cells (osteoblasts, osteocytes, and osteoclasts) and a mineralized extracellular matrix that is primarily made up of collagen fibrils and hydroxyapatite crystals. Ossification, or bone formation, begins with a framework that consists of either mesenchymal connective tissue (intramembranous ossification) or cartilage (endochondral ossification). Woven bone is formed, which is replaced by the more solid and layered lamellar bone. The outer cortical layers can be macroscopically differentiated from the branched center of the trabeculae.
Function of bone
- Supportive function
- Protective function
- Storage (calcium and phosphorus reservoir)
Types of bone
Long bones: include the femur, humerus, ulna, radius, fibula, metacarpals, and phalanges
- Metaphysis: area between the epiphysis and the diaphysis
- Apophysis: large bony projections where ligaments and tendons attach
- Short bones: include tarsal and carpal bones
- Flat bones
- Bones that develop within tendons (e.g., the patella)
- Function to reduce friction of the tendon and to reduce excessive wear
- Irregular bones
The exact composition or organization of individual bone components differs in the various bones types and maturation stages. All human bones are composed of the same basic elements:
- Bone cells: build and remodel bones
- Bone matrix: composed of organic and inorganic components
- Bone membranes: cover the inner and outer surface of the bone
- Bone marrow: either actively involved in hematopoiesis (red bone marrow) or primarily replaced by adipose cells (yellow bone marrow)
|Characteristics of bone cells|
|Osteoprogenitor cells|| || |
|Osteoblasts || |
|Osteoclasts|| || |
Composed of organic and inorganic material:
- Periosteum: a membrane of connective tissue that covers the outer surface of the bone in two distinct layers
Development and maturation
Development of bone
- Bone is derived from mesoderm.
|Overview of the ossification process|
|Endochondral ossification||Intramembranous ossification|
|Process|| || |
The skull undergoes both processes: some bones (e.g., frontal, parietal bones) are derived from the neural crest and undergo membranous ossification, whereas other bones (e.g., sphenoid, occipital bones) are derived from the paraxial mesoderm and undergo endochondral ossification.
Bones are arranged into woven bone (primary bone) during embryonic development or bone healing. The structure of woven bone is disorganized and transformed into organized tissue of lamellar bone (secondary bone) through continuous remodeling.
|Stages of bone maturity|
|Woven bone||Lamellar bone|
|Remodeling|| || |
Trabecular bone (spongy or cancellous bone)
- Definition: thin lattice-shaped (trabeculae) units inside the lamellar bone
Cortical bone (compact bone)
- Definition: homogeneous and dense cortical layer of lamellar bone
- Interstitial lamellae
- Circumferential lamellae: provide an outer and inner boundary for the cortical bone through at least one lamellar layer
Lamellar bones vascularization and canals
- Bone canals and associated vessels
Development of long bones
Primary ossification center: diaphysis
- Secondary ossification center: epiphysis
Longitudinal growth of the long bones
- Chondrocyte proliferate at the epiphyseal plates → longitudinal growth with the epiphysis pushed away from the diaphysis
- Cartilage tissue is degraded and remodeled in bone tissue from the medullary cavity.
- The proliferation zone progresses with the same velocity as the ossification zone.
- Chondrocytes cease proliferating and bone replaces cartilage (ossification zone) in a process known as epiphyseal fusion.
- Zone of resting cartilage: deposits undifferentiated precursor chondrocytes that provide the proliferation zone with new chondrocytes
Proliferation zone: mitosis of chondrocytes
- Proliferation process
- Vertical (from an isogenic neighbor): transverse septum
- Horizontal (from nonisogenic neighbors): longitudinal septum
- Zone of hypertrophy: enlarges cartilage through chondrocyte hypertrophy, which leads to collagen (type X) production by hypertrophic chondrocytes and mineralization of the longitudinal septa
Zone of calcification
- Mineralized columns remain (ossified longitudinal septa).
- Approx. ⅓ of the longitudinal septa is retained, and the remaining septa is degraded by chondroclasts.
- Zone of ossification: colonization of the mineralized longitudinal septae by osteoblasts → osteoid formation → mineralization
Bone remodeling and healing
The human skeleton is in a continuous dynamic state of remodeling. Not only does this apply to the replacement of immature woven bone by lamellar bone, but also for adaptation of adult bones to their individual load.
Bone remodeling 
- Cells involved
- Duration: usually longer than the lifespan of the cells involved (continual replacement of involved cells)
Blasts build, clasts crumble.
- Osteoclasts are followed by osteoblasts → deposition of the first osteoid layer in the tunnel
- Additional osteoblasts follow and deposit osteoid onto the first osteoid layer → osteoblasts of the first layer are walled in → osteoblasts become osteocytes
- The deposition process is repeated until the tunnel is almost full → central remains open
- The innermost (i.e., last) generation of osteoblasts is no longer walled in → cells return to their resting state and form the endosteum
Mineralization: occurs successively
- Osteoblasts secrete collagen and vesicles into the extracellular matrix.
- Vesicles contain enzymes (e.g., alkaline phosphatase), which increase local phosphate levels (e.g., by cleavage of pyrophosphate).
- Calcium-binding molecules in the vesicles most likely serve as a focal point.
- Initial formation of hydroxyapatite crystals around the focal point in the vesicles
- Independent growth of the crystals until penetration of the vesicle membrane
- Release of crystals in the extracellular matrix
- Growth of crystals in the extracellular matrix and accumulation of collagen fibrils
- Osteoclasts organize in Howship lacunae (small depressions on the trabecular bone surface). They move to resorb trabecular bone and form a tight seal around the resorption area.
- Osteoclasts produce protons via the enzyme carbonic anhydrase.
- Secretion of chloride ions (passive) and protons (active, via ATPase) in Howship lacunae, with the formation of an acidic environment (∼ pH 4.5) → dissolution of inorganic bone elements
- Secretion of lysosomal enzymes (especially cathepsin K and ) → degradation of organic bone elements
- Endocytosis/transcytosis of the bone elements
Regulation of bone remodeling 
- RANK (): receptor on osteoclasts and osteoclast precursors, for interaction with osteoblasts
- RANKL )
- Osteoprotegerin (OPG)
- M-CSF ()
- Load on the bone leads to increased bone mass.
- Absence of load (e.g., due to being confined in bed) results in decreased bone mass.
- Negative feedback by osteoclasts: growth factors are embedded in the bone matrix and are released during degradation by osteoclasts → osteoblasts stimulation
- PTH effects
- Inhibits apoptosis of osteoblasts, leading to increased bone formation
- Stimulates apoptosis of osteoclasts, leading to decreased bone resorption
- Stimulates closure of the epiphyseal plate in puberty
- (e.g., postmenopausal or after bilateral oophorectomy) leads to increased bone resorption, which can result in osteoporosis.
- Vitamin D
Bone healing 
- Primary bone healing
Secondary bone healing
- Occurs when the distance of the fracture ends is larger
- Initial bridging of the fracture gap is formed with connective tissue or cartilage (fibrocartilage callus).
- Conversion to woven bone (bony callus) by endochondral ossification
- Over the course of months, woven bone is slowly remodeled into resilient lamellar bone.
- Pseudoarthrosis: can occur if the healing process is permanently disturbed by motion of the fracture ends (e.g., through insufficient immobilization)
During childhood or adolescence, a fracture near a joint may damage the unclosed epiphyseal plate, which can result in growth disorders (e.g., asymmetry, inhibition, acceleration) during healing.