SM_233a: Metabolic Disease Flashcards
Describe the normal skeletal system
Normal skeletal system
- 60-70% is inorganic matrix (calcium hydroxyapatite)
- 30% is composed of organic elements (90% collagen type I) including osteocalcin (most abundant noncollagen protein/important for bone mineralization and acts as serum marker of bone formation and density)
- Numerous growth factors including osteoblast-activating Transforming Growth Factor beta (TGF-beta) and bone morphogenic protein (BMP)
- Cellular components: osteoblasts, osteocytes, and osteoclasts
Outside of bone is made of _____ bone while inside is made of _____
Outside of bone is made of cortical/lamellar bone while inside is made of spongy/trabecular/cancellous bone
Describe intramembranous bone formation
Intramembranous bone formation
- Develops from collagen (collagen modeled bone)
- Forms flat bones of skull and clavicles
- Periosteal osteoprogenitor cells form osteoblasts and responsible for prepubertal thickening of cortex and bone widening (appositional bone growth)
Describe enchondral bone formation
Enchondral bone formation
- Develops from epiphyseal cartilage of the growth plate (cartilage modeled bone)
- Forms appendicular and axial skeleton and responsible for prepubertal bone lengthening
Enchondral bone formation is responsible for development of _____ skeleton
Enchondral bone formation is responsible for development of appendicular skeleton
(perturbations/arrest in normal endochondral ossification lead to many congenital and metabolic bone diseases)
____, ____, ____, and ____ stimulate cartilage growth in the zone of proliferation in enchondral bone formation
IHH, PTHrP, BMP, and ILGF-1 stimulate cartilage growth in the zone of proliferation in enchondral bone formation
____ inhibits cartilage growth in the zone of proliferation during enchondral bone formation
FGF inhibits cartilage growth in the zone of proliferation during enchondral bone formation
_____ and _____ are immature bone
Osteoid and woven bone are immature bone
____ is mature bone
Lamellar bone is mature bone
Osteoid is ______
Osteoid is unmineralized poorly organized bone matrix (Type I collagen) formed rapidly
(immature, becomes adult bone once mineralized)
Woven bone is _____
Woven bone is mineralized immature bone formed rapidly and the main component of prepubertal bone
Mineralized mature bone forms ____ and has ____ parallel ____ fibers and evenly distributed ____
Mineralized mature bone forms slowly and has parallel collagen type I fibers (lamellae) and evenly distributed osteocytes
Cortical (compact bone) involves _____, _____, and _____
Cortical (compact bone) involves collagen first deposited in circumferential lamellae, dissipation of mechanical stress via osteon formation, and collagen deposition around Haversian canals as concentric lamellae
Cancellous (spongy) bone is formed by ____ and involves deposition of ____
Cancellous (spongy) bone is formed by enchondral ossification and involves deposition of collagen in longitudinal lamellae
Cellular elements of bone are ____, ____, and ____
Cellular elements of bone are osteoblasts, osteocytes, and osteoclasts
Describe osteoblasts
Osteoblasts
- Derived from mesenchymal stem cells & line surface of bone
- Cell surface receptors include PTH, Vitamin D, estrogen, and others
- Produce matrix proteins and type I collagen and initiate mineralization
Describe osteocytes
Osteocytes
- Osteoblasts that are incorporated into mature bone (most common cells in bone)
- Produce sclerostin: protein that inhibits further bone formation until osteocytes are stimulated
Describe osteoclasts
Osteoclasts
- Multinucleated giant cells formed from monocytic progenitor cells in response to RANK-ligand secreted from osteoblasts and bone stromal cells
- Responsible for bone resorption
- Located in resorption pits / Howship’s lacunae
Osteoblasts contain ____, while osteoclast precursors contain ____
Osteoblasts contain RANK-L, while osteoclast precursors contain RANK
(binding together activates osteoclast so it can reabsorb bone)
Binding of RANK-L from osteoblasts to RANK on osteoclast precursors ____
Binding of RANK-L from osteoblasts to RANK on osteoclast precursors activates osteoclasts so they can reabsorb bone
Describe the osteoclast resorption pit
Osteoclast resorption pit
- Forms a sealed acidified microenvironment in the resorption pits on the surface of bone
- Ruffled membrane contains H+ ATPase (mutations in H+ ATPase are most common cause of osteopetrosis)
- HCl mobilizes the mineral phase and proteinase cathepsin K degrades the organic matrix (type I collagen) -> releases minerals and growth factors from bone
Mutations in the ____ in the osteoclast resorption pit are the most common cause of osteopetrosis
Mutations in the H+ ATPase in the osteoclast resorption pit are the most common cause of osteopetrosis
Balanced interaction between ____ and ____ ensures normal bone structure through appropriate ____ in response to mechanical stress
Balanced interaction between osteclasts and osteblasts ensures normal bone structure through appropriate bone remodeling in response to mechanical stress
Bone remodeling is ____
Bone remodeling is a continuous process that dissipates bone stress throughout the life of the individual
Bone remodeling in cortical bone involves ____
Bone remodeling in cortical bone involves Haversian system with osteon formation
Bone remodeling in cancellous bone involves ____
Bone remodeling in cancellous bone involves activation of osteoclasts and resorption of bone in Howship’s lacuna, then reversal of cell type (osteoblasts replace osteoclasts) leading to bone formation
Describe osteon formation in cortical bone
Osteon formation in cortical bone
- Osteons created in response to stress: aggregates of osteclasts form “cutting cones” and resorb bone (primary osteon) -> osteoblasts fill cavity with bone deposited in concentric lamellae
- Osteocytes within rings of the osteon communicate through dendritic processes and regulate bone remodeling and mineral stores
Describe bone remodeling in trabecular bone
Bone remodeling in trabecular bone
- Activation of osteoclasts
- Resorption of bone in Howship’s lacuna
- Reversal of cell type to osteoblasts
- Bone formation
Describe acute osteomyelitis
Acute osteomyelitis
- Caused mainly by bacterial infection resulting from hematogenous spread, contiguous spread from abscess or ulcer, direct inoculation of organism into bone, and ischemia (vascular insufficiency)
- Staphylococcus aureus is most common infectious agent
- Microscopically acute inflammatory cells are initimately associated with non-viable bone
- Periosteum/endosteum responds by forming new bone (involucrum, star top) around dead infected bone
- Managed by surgery and long course antibiotic therapy
Categories of bone diseases include ____, ____, ____, ____, and ____
Categories of bone diseases include abnormal matrix, too little matrix, too little mineralization, too much bone resorption, and too little bone resorption
Osteogenesis imperfecta involves an _____ matrix
Osteogenesis imperfecta involves an abnormal matrix
Describe osteogenesis imperfecta
Osteogenesis imperfecta
- Defect in synthesis of Type I collagen: abnormal Type I collagen results in more serious disease than decreased synthesis of collagen
- Excess callus formation after fractures
- Blue sclera
Osteogenesis imperfecta involves a defect in synthesis of _____, excess _____ formation after fractures, and _____
Osteogenesis imperfecta involves a defect in synthesis of Type I collagen, excess callus formation after fractures, and blue sclera
Osteoporosis has ____ matrix
Osteoporosis has too little matrix
Describe osteoporosis
Osteoporosis
- Bone that is histologically normal but decreased in quantity
- ≥ 1 atraumatic fractures or low bone mineral density on DEXA
- Can be localized: immobility, Sudeck’s atrophy, inflammatory focus around bone such as in rheumatoid arthritis
- Generalized: senila and post menopausal osteoporosis
Describe the pathogenesis of senile and postmenopausal osteoporosis
Senile and postmenopausal osteoporosis pathogenesis
- Depends upon initial bone density and subsequent loss of bone that occurs wirth age
- Bone mass peaks in early adulthood
- With aging, osteblasts lose ability to form new bone and growth factors lose potency
- Bone loss accentuated by activation of osteoclasts
Describe postmenopausal osteoporosis
Postmenopausal osteoporosis
- Estrogen deficiency upregulates osteoclastogenic factors and decreases OPG resulting in osteoclastogenesis
- Affects bones with large surface area - fracture of vertebra and wrist
- High-turnover: activity of osteoclasts > osteoblasts
Describe senile osteoporosis
Senile osteoporosis
- Men and women > 70 years of age
- Caused by osteoblasts having decreased reproductive/biosynthetic potential with age and growth factors in matrix losing potency
- Fractures involve hip and vertebra
- Low-turnover: activity of osteoblasts low, normally active osteoclasts
Postmenopausal osteoporosis is _____-turnover, while senile osteoporosis is _____-turnover
Postmenopausal osteoporosis is high-turnover, while senile osteoporosis is low-turnover
- High-turnover osteoporosis: activity of osteoclasts > osteoblasts (which are active)
- Low-turnover osteoporosis: activity of osteoblasts low, normally active osteoclasts
Mucopolysaccharidoses are caused by mutations in ____, resulting in ____ and ____
Mucopolysaccharidoses are caused by mutations in lysosomal enzymes that degrade glycosaminoglycans, resulting in their accumulation and cellular damage
Describe clinical signs and symptoms of mucopolysaccharidoses
Clinical signs and symptoms of mucopolysaccharidoses
- Vary according to enzyme defect
- Include cardiac valvular disease, mental retardation, hepatosplenomegaly, corneal clouding, umbilical/inguinal hernai, coarse facies, macroglossia, and enlarged gingiva
Describe changes in bone and soft tissue in mucopolysaccharidoses
Changes in bone and soft tissue in mucopolysaccharidoses
- Fibroblasts (tendons/ligaments), chondrocytes, osteoblasts, and osteoclasts
- Defects in enchondral ossification lead to short stature, kyphosis/scoliosis, odontoid hypoplasia with risk of spinal cord compression and hypoplastic teeth
- Abnormal intramembranous ossification leads to macrocephaly
- Abnormal bone remodeling and enchondral ossification result in osteoporosis
- Accumulation of GAG in tendons/ligaments of joints induces inflammation resulting in periarticular fibrosis, joint stiffness and/or hypermobility, and later secondary osteoarthritis
Vitamin D deficiency (rickets/osteomalacia) involves ____
Vitamin D deficiency (rickets/osteomalacia) involves too little mineralization
Describe Vitamin D deficiency (rickets / osteomalacia)
Vitamin D deficiency (rickets / osteomalacia)
- Lack of calcification of growth plate (rickets) or of osteoid to form new adult bone (osteomalacia)
- Increased PTH and decreased serum phosphate stimulate Vitamin D synthesis -> negative feedback
Metaphyseal flare is indicative of _____
Metaphyseal flare is indicative of rickets
- Vitamin D deficiency in children -> growth plate widens with cartilage
Radiographs of rickets show _____, _____, and _____
Radiographs of rickets show femoral bowing, metaphyseal flaring, and rosary rickets (enlarged costochondral junctions in rib cage)
Describe osteomalacia
Osteomalacia
- Inability to calcify osteoid to form new adult bone during remodeling
- Usually due to chronic renal failure
- Results in insufficiency fractures on X-ray and bone pain
Osteomalacic bone shows _____
Osteomalacic bone shows excess osteoid
Hyperparathyroidism involves ____
Hyperparathyroidism involves too much bone resorption
Clinically hyperparathyroidism involves ____, ____, ____, and ____
Clinically hyperparathyroidism involves (GI tract) moans, bones, (renal) stones, and psychiatric overtoens
Hyperparathyroidism pathogenesis includes ____ and ____, resulting in ____
Hyperparathyroidism pathogenesis includes primary HPT (parathyroid adenoma followed by chief cell hyperplasia) and secondary HPT (parathyroid hyperplasia due to chronic renal failure), resulting in osteoclastogenesis and osteoporosis
(affects cortical > cancellous bone - bone loss in fingers and clavicles on X-ray)
Hyperparathyroidism involves bone loss in ____ and ____ on X-ray
Hyperparathyroidism involves bone loss in fingers and clavicles on X-ray
(subperiosteal resorption)
In hyperparathyroidism, activated osteoclasts form ____ that reabsorb bone and there is ___ and also ___
In hyperparathyroidism, activated osteoclasts form “cutting cones” and there is dissecting osteitis (railroad track appearance of bony trabeculi due to central reabsorption of osteoclasts) and also subperiosteal cortical bone resorption by osteoclasts
Features of hyperparathyroidism are ____ and ____
Features of hyperparathyroidism are dissecting osteitis and brown tumor of bone (osteitis fibrosa cystica)
- Dissecting osteitis: aggreates of activated osteoclasts form a cutting cone along the longitudinal axis of a trabecula
- Brown tumor of bone (osteitis fibrosa cystica): spindled stromal cells, osteoclasts, foci of hemorrhage, and hemosiderin deposits
Paget’s disease involves _____ bone resorption
Paget’s disease involves too much bone resorption
Paget’s disease is defined as ____
Paget’s disease is defined as collage of matrix madness due to dyssynchrony of osteoclastic/osteoblastic activity
Paget’s disease pathogenesis involves ____
Paget’s disease pathogenesis involves upregulation of NF-kappaB osteoclastogenesis
Paget’s disease manifests as _____ on X-ray
Paget’s disease manifests as characteristic tapering lytic process in distal femur
(osteolytic phase w/ enlarged oseoclasts, then osteosclerotic phase with thickened bone with a haphazard pattern of cement lines)
Osteopetrosis involves ____ bone resorption
Osteopetrosis involves too little bone resorption
Osteopetrosis involves ____ osteoclast activity, resulting in _____ bone
Osteopetrosis involves absent/defective osteoclast activity, resulting in abnormally thickened bone
(often osteoclasts fail to acidify resorption pits)
Osteopetrosis manifests as _____ on X-ray
Osteopetrosis manifests as sclerotic medullary cavity on X-ray
(bones lack medullary canal)
(medullary hematopoietic bone marrow replaced by calcified cartilage and new bone)
