2.6.4. PATH LAB - Bone Pathology I (Part 1 of 3) Flashcards
The bone matrix serves a repository for what?
99% of the body’s calcium and 85% of its phosphorous
What are caniculi?
Osteocytes are interconnected by an intricate network of dendritic cytoplasmic processes through tunnels known as canaliculi.
What are osteoclasts?
Osteoclasts are specialized multinucleated macrophages derived from circulating monocytes that are responsible for bone resorption.
What are osteoblasts?
Osteoblasts, located on the surface of the matrix, synthesize, transport, and assemble the matrix and regulate its mineralization
What is endochondral ossification?
During embryogenesis, most bones develop from a cartilage mold by the process of endochondral ossification.
Endochondral ossification process progressively deposits new bone at the bottom of the growth plate, resulting in longitudinal growth.
What is intramembranous ossification?
Responsible for the development of flat bones
For example, bones of the cranium are formed by osteoblasts directly from a fibrous layer of tissue that is derived from mesenchyme, without a cartilage anlagen.
Enlargement of bones is achieved by the deposition of new bone on a pre-existing surface
Effect of Growth factor on bone?
Growth hormone (GH) is secreted by the anterior pituitary and acts on resting chondrocytes to induce and maintain proliferation
Thyroid hormone on bone?
Thyroid hormone (T3) is secreted by the thyroid gland and acts on proliferating chondrocytes to induce hypertrophy
Indian hedgehog?
Indian hedgehog (Ihh) is locally secreted and made by prehypertrophic chondrocytes. It coordinates chondrocyte proliferation and differentiation
What is Parathyroid hormone related protein?
Parathyroid hormone related protein (PTHrP) is a local factor expressed by perichondrial stromal cells and early proliferating chondrocytes. it activates the PTH receptor and maintains proliferation of chondrocytes
What is Wnt?
Wnt is a family of secreted factors that are expressed at highest levels in the proliferating zone and bind to the receptors Frizzled and LRP5/6
What is SOX9?
SOX9 is a transcription factor expressed by proliferating but not hypertrophic chondrocytes that is essential for differentiation of precursor cells into chondrocytes.
What is RUNX2?
RUNX2 is a transcription factor involved in chondrocyte and osteoblast differentiation. It is expressed in early hypertrophic chondrocytes and immature mesenchymal cells and controls terminal chondrocyte and osteoblast differentiation, respectively
What is Fibroblast growth factor?
Fibroblast growth factors (FGFs) are secreted by a variety of mesenchymal cells. FGF (most notably FGF3) acts on hypertrophic chondrocytes to inhibit proliferation and promote differentiation.
What is the Achondroplasia mutation?
Achondroplasia = mutation in FGFR3 (FGF Receptor 3)
What are Bone Morphogenic proteins?
Bone morphogenic proteins (BMPs) are members of the TGF-β family. They are expressed at various stages of chondrocyte development in the growth plate and have diverse effects on chondrocyte proliferation and hypertrophy.
Where does bone remodeling take place?
Remodeling takes place at a microscopic locus known as the bone (or basic) multicellular unit (BMU).
What is the sequence of events for bone remodeling?
Sequence: Osteoclast attachment ⇒ Resorption ⇒ Osteoblast attachment ⇒ Proliferation ⇒ Matrix synthesis
What are the three factors of the RANK pathway?
RANK, RANKL, OPG
What cell expresses RANK?
Transmembrane receptor RANK (receptor activator for NF-κΒ) - expressed on osteoclast precursors
What cell expresses RANKL?
RANK ligand (RANKL) - expressed on osteoblasts and marrow stromal cells
What is OPG?
Osteoprotegerin (OPG) - a secreted “decoy” receptor that can bind RANKL and prevent its interaction with RANK
Describe the RANK pathway mechanism
When stimulated by RANKL, RANK signaling activates the transcription factor NF-κΒ, which is essential for the generation and survival of osteoclasts.
What is MCSF and what makes it?
Monocyte colony stimulating factor (M-CSF) - produced by osteoblasts
Describe the M-CSF pathway
Activation of the M-CSF receptor on osteoclast precursors stimulates a tyrosine kinase cascade that is also crucial for the generation of osteoclasts.
Describe the WNT/β-catenin Pathway
WNT proteins produced by osteoprogenitor cells bind to the LRP5 and LRP6 receptors on osteoblasts, triggering the activation of β-catenin and production of OPG
The balance between net bone formation and resorption is modulated by what?
The balance between net bone formation and resorption is modulated by the signals that connect to the RANK and WNT signaling pathways.
Effect of parathyroid hormone, IL-1 and glucocorticoids on bone?
Parathyroid hormone, IL-1 and glucocorticoids promote osteoclast differentiation and bone turnover.
Effect of sex hormones or bone morphogenic proteins on bone?
Bone morphogenic proteins and sex hormones (ex. estrogen) generally block osteoclast differentiation or activity by favoring OPG expression.
This is one of the reasons that postmenopausal women are more susceptible to osteoporosis - their estrogen levels have dropped
Dysostosis vs. Dysplasia
Developmental anomalies can result from localized problems in the migration and condensation of mesenchyme (dysostosis) or global disorganization of bone and/or cartilage (dysplasia).
Achondroplasia
What is the affected molecule and clinical phenotype?
Receptor
Short stature, rhizomelic shortening of limbs, frontal bossing, midface deficiency
Osteopetrosis (autosomal dominant)
What is the affected molecule and clinical phenotype?
Receptor
Increased bone density, hearing loss, skeletal fragility
Osteopetrosis (infantile form)
What is the affected molecule and clinical phenotype?
Receptor ligand
Increased bone density
Osteogenesis Imperfecta I
What is the affected molecule and clinical phenotype?
Type I collagen
Bone fragility
Major cause of dwarfism?
Achondroplasia
What causes Achondroplasia genetically?
Caused by gain-of-function mutations in the FGFR3: Normally FGF-mediated activation of FGFR3 inhibits endochondral growth. Constitutive activation of FGFR3 exaggerates this effect, suppressing growth.
What allele is linked to the mutations associated with Achondroplasia?
Almost all mutations stem from the paternal allele; there is evidence linking frequency of mutation with advanced paternal age.
What is thanatophoric dysplasia and how does it present?
Thanatophoric dysplasia is the most common lethal form of dwarfism, affecting about 1 in every 20,000 live births.
The under-developed thoracic cavity leads to respiratory insufficiency.
Osteopetrosis vs. osteoporosis
Abnormal bone density can result from mutations in genes that regulate osteoclast differentiation or osteoclast function
Such mutations can either cause osteoporosis (too little bone) or osteopetrosis (too much bone)
What causes Osteogenesis Imperfecta, what is its associated abnormality?
Osteogenesis Imperfecta (OI), or brittle bone disease, is a phenotypically diverse disorder caused by deficiencies in the synthesis of type I collagen.
The fundamental abnormality in OI is too little bone, resulting in extreme skeletal fragility.
How does Osteogenesis imperfecta present?
Blue sclerae are caused by decreased collagen content, making the sclera translucent and allowing partial visualization of the underlying choroid
Hearing loss is common (because the bones of the ear are also fragile)
Dental imperfections (small, misshapen, blue/yellow teeth) are also common
Type 1 vs. Type 2 osteogenesis imperfecta
The Type 2 variant is uniformly fatal in utero or during the prenatal period.
Patients with the Type 1 variant usually have a normal lifespan but experience childhood fractures that decrease in frequency after puberty (Injuries often mimic child abuse)
What are osteopetrosis conditions? What causes it? What do the bones look like?
Osteopetrosis, also known as marble bone disease and Albers-Schonberg disease, refers to a group of rare genetic diseases that are characterized by reduced bone resorption and diffuse symmetric skeletal sclerosis due to impaired formation or function of osteoclasts.
Bones are large but abnormally brittle
Discuss the pathogenesis of osteopetrosis, what mechanism tends to cause it?
Pathogenesis: Most of the mutations underlying osteopetrosis interfere with the process of acidification of the osteoclast resorption pit, which is required for the dissolution of the calcium hydroxyapatite within the matrix
What is one associated enzyme mutation linked to osteopetrosis?
Carbonic anhydrase II mutation leads to loss of the acidic microenvironment required for bone resorption
Renal tubular acidosis is seen with carbonic anhydrase II mutation (lack of carbonic anhydrase results in decreased tubular reabsorption of HCO3-, leading to metabolic acidosis)
Bone morphology of osteopetrosis
Due to deficient osteoclast activity, bones involved by osteopetrosis lack a medullary canal, and the ends of long bones are bulbous and misshapen.
Deposited bone is not remodeled and tends to be woven in architecture.
Treatment for osteopetrosis?
Treatment: Bone marrow transplant,
which is effective because osteoclasts are derived from hematopoietic precursors. The normal osteoclasts produced from donor stem cells reverse many of the skeletal abnormalities
What are Mucopolysaccharidoses? What do they cause?
Group of lysosomal storage diseases that are caused by deficiencies in degradation enzymes.
Mesenchymal cells, especially chondrocytes, normally degrade extracellular matrix mucopolysaccharides. In these diseases, mucopolysaccharides accumulate inside the chondrocytes, causing apoptotic death of the cells, and also in the extracellular space, resulting in structural defects in articular cartilage.
Osteopenia vs. osteoporosis?
The term osteopenia refers to decreased bone mass, and osteoporosis is defined as osteopenia that is severe enough to significantly increase the risk of fracture
What are the most common forms of osteoporosis?
The most common forms of osteoporosis are the senile and postmenopausal types
When is peak bone mass reached? What affects it?
Peak bone mass is achieved during young adulthood (~30 years old)
Largely determined by hereditary factors.
Physical activity, muscle strength, diet, and hormonal state also make important contributions
Relate decreased estrogen levels to osteoporosis
Decreased estrogen levels after menopause actually increase both bone resorption and formation but the latter does not keep up with the former, leading to high-turnover osteoporosis.
Effect of osteoporosis on Haversian systems?
In senile osteoporosis, the cortex is thinned by subperiosteal and endosteal resorption and the Haversian systems are widened.
Gold standard for detection of osteoporosis?
Gold standard for detection of osteoporosis: Dual-energy x-ray absorptiometry (DEXA)
Osteoporosis lab values
LAB VALUES: Serum calcium, phosphate, PTH, and alkaline phosphatase are NORMAL; labs help to EXCLUDE osteomalacia, which has a similar clinical presentation
What is Paget’s disease?
Paget disease is a disorder of increased, but disordered and structurally unsound, bone mass.
What are the three stages of Paget’s disease?
Initial osteolytic stage
Mixed osteoclastic-osteoblastic stage
Osteoblastic
When is the diagnosis typically for Paget’s disease?
Usually begins in late adulthood (average diagnosis is ~70 years old)
Mutations in the SQSTM1 gene increase the activity of NF-κΒ, which does what?
Mutations in the SQSTM1 gene increase the activity of NF-κΒ, which increases osteoclast activity
Morphology of bone in Paget’s Disease?
Hallmark is mosaic pattern of lamellar bone, seen in the sclerotic phase.
This jigsaw puzzle appearance is produced by unusually prominent cement lines, which join haphazardly oriented units of lamellar bone.
What happens to the face and head with PAget’s Disease?
Enlargement of the craniofacial skeleton may produce leontiasis ossea (lion face)
Increased hat size (skull is commonly affected)
Can cancer develop in Paget’s Disease?
Though rare, sarcomas can develop due to the increased proliferation of osteoclasts.
Lab values for Paget’s?
LAB VALUES: Isolated elevated alkaline phosphatase (MOST COMMON cause of isolated elevated alkaline phosphatase in patients over 40)
What causes Rickets and Osteomalacia?
Both are caused by either vitamin D deficiency or its abnormal metabolism (Vitamin D is a fat soluble vitamin)
Fundamental defect in Rickets and Osteomalacia
Fundamental defect is an impairment of mineralization and a resultant accumulation of unmineralized matrix
What is rickets specifically?
Rickets refers to the disorder in children (primarily affects growth plates)
Pigeon-breast deformity, frontal bossing (enlarged forehead), rachitic rosary at costchondral junction, bowing of the legs
Lab Results for Rickets
LABS: Low serum calcium and phosphate values
What is osteomalacia specifically and what lab values do we typically see?
Osteomalacia refers to the disorder in adults (remodeled bone is undermineralized)
LABS: low serum calcium, low serum phosphate, elevated PTH and elevated alkaline phosphatase
Hyperparathyroidism leads to what?
Hyperparathyroidism leads to significant skeletal changes related to unabated osteoclast activity
Untreated hyperparathyroidism manifests with three unrelated abnormalities:
Untreated hyperparathyroidism manifests with three unrelated abnormalities: osteoporosis, brown tumors, and osteitis fibrosa cystica.
von Recklinghausen disease of bone?
The combination of increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors is the hallmark of severe hyperparathyroidism and is known as generalized osteitis fibrosa cystica (von Recklinghausen disease of bone).
What is Renal Osteodystrophy?
Collectively the skeletal changes that occur in chronic renal disease, including those associated with dialysis
What is aplastic disease?
Low turnover of bone
Pathogenesis of Renal Osteodystrophy
Tubular dysfunction ⇒ renal tubular acidosis ⇒ low pH causes demineralization of the bone matrix
How can bone issues come up with renal failure?
Generalized renal failure ⇒ reduced phosphate excretion ⇒ secondary hyperparathyroidism
