Basic Science Flashcards
What are canaliculi within bone?
System within the lacunar network used by osteocytes to communicate with each other.
What are Haversian canals?
Found in the center of an osteon in compact bone. They contain blood vessels and nerves.
What are Volkmann canals?
They run perpendicular to Haversian canals and connect them to each other.
Mechanism of Rituximab?
Monoclonal antibody to CD20 antigen (inhibits b cells) Used in Rheumatoid patients who are intolerant to methotrexate or DMARDs
Mechanism of Etanercept?
TNF alpha antagonist Tumor necrosis factor receptor immunoglobulin G fusion protein.
What is the mechanism of Methotrexate?
folic acid analogue Binds to dihydrofolate reductase and prevents synthesis of tetrahydrofolate. Usually first line treatment for Rheumatoid.
True or false chlorhexidine gluconate wash the night before surgery decreases surgical site infection?
False.
What bacteria is of concern with soil contamination? What abx coverage should be added?
Clostridia botulinum (anaerobic gram positive bacilli) High dose penicillin
What are the zones of the physis?
What zone of the physis do Salter-Harris fractures occur through?
Hypertrophic zone. Specifically the Zone of calcification within the hypertrophic zone.
Hypertrophic zone can be subdivided into zones of maturation, degeneration, and calcification.
Mechanism of acetominophen?
inhibits prostaglandin E2 production through interleukin-1 beta.
exerts its effects on the central nervous system.
What is the mechanism of fluoroquinolones?
inhibition of DNA gyrase.
What is released from cells within a joint that causes articular surface damage in septic arthrits?
proteolytic enzymes
such as matrix metalloproteinases(MMP)
Have also been implicates in rheumatoid and osteoarthritis.
Toll like receptors such as TRL-2 activate NF-kB pathway that leads to production of MMPs.
What is the most common cause of septic arthritis in adolescents?
Neisseria gonorrhoeae
Gram negative diplococci.
Patients usually have preceding migratory polyarthralgia, multiple joints involved, and small red papules.
Gram stain is negative over 50% of the time.
What will you see on histology from the tissue surrounding a metal on metal hip that has Delayed Type Hypersensitivity?
diffuse infiltrates of both T and B lymphocytes.
What is the function of Osteoprotegrin?
Limits the activity of RANKL.
This promotes osteoblast activity and increases bone formation.
What is Osteonectin?
Secreted by platelets and osteoblasts and functions to regulate calcium and organzing mineral in the bone matrix.
What affect do Bone morphogenic proteins have on inervertebral disk cells and matrix synthesis?
Increase chondrogenic phenotype expression
Increase matrix syntheis.
What causes tumoral calcinosis?
What is the main laboratory abnormaility?
What gentic abnormality is most common?
pathologic deposition of calcium adjacent to joints and occurs in the presence of phosphate dysregulation.
Hyperphosphatemia
FGF-23
Defect in isocitrate dehydrogenase 1 can cause what syndrome?
Maffucci’s syndrome
Deficiency in alpha-1 hydroxylase can lead to?
Hypovitaminosis D.
Genetic defect in Activin A receptor type 1 has been linked to?
Fibrodysplasia ossificans progressiva.
Abnormal ossification of connective tissue at a young age.
What is the function of Linezolid?
prevents the formation of the initiation complex between the 30S and 50S subunits of the ribosome.
Unique in that it disrupts protein synthesis at its origin.
Binds to the 50s subunit of the bacterial ribosome preventing the formation of the initiation complex.
Describe the mechanism of action of the following antibiotics?
Lenezolid
Aminoglycosides
Macrolides
Tetracycline
Chloramphenicol
What is the inheritance pattern of neurofibromatosis?
What embryonic structure is it a disorder of?
What is the mutation of?
autosomal dominant.
neural crest.
Mutated neurofibromin(NF1) gene on chromosome 17q21.
What is the most common genetic disorder caused by a new mutation of a single gene?
Neurofibromatosis type I
On a histology slide how do you differentiate acute vs chronic osteomyelitis?
Acute has live osteocytes(have nuclei) and neutrophils.
Chronic has no nuclei in the osteocytes and lymphocytes. Also has fibrosis of marrow.
What gene mutation is associated with congenital vertical talus?
HOXD10 gene mutation
(transcription factor)
What should be on your differential for congenital vertical talus?
How can you tell the difference between the two?
Oblique talus
the talonavicular subluxation reduces with forced plantarflexion of the foot.
Treatment is observation and shoe inserts. Only some will require pinning.
What two characteristic physical exam findings are found in congenital vertical talus?
rigid rockerbottom deformity
prominent talar head.
What is a normal talocalcaneal angle?
20-40 degrees
> 40 is associated iwth congenital vertical talus.
Olbique talus will reduces with forced dorsiflexion.
Do you need an MRI for congenital vertical talus?
Yes!
Not for the foot but neuraxial imaging should be perfomred to rule out neurologic disorders.
Treatment for a congenital vertical talus?
When?
Serial manipulation can be performed but this is just pre-operative. Still require surgery. Done to stretch dorsolateral soft tissue stuctures. Foot placed in inversion and plantarflexion.
Treatment should be performed as early as possible(6-12 months).
Surgical release, reduction, and pinning: Plantar release, lengthening of peroneals, achilles, and toe extensors. Tib ant transfer to talar neck.
What do you do for a 12 year old with a missed vertical talus?
triple arthrodesis
What do you after excision of an accessory navicular with the tenond that is relfected?
Do not advance the posterior tibial tendon.
Increases downtime and morbidity.
What is a calcaneovalgus foot?
benign soft tissue contracture deformity characterized by hindfoot eversion and dorsiflexion.
Not a congential deformity or dislocation.
Passiviely correctable. One way you differentiate it from vertical talus.
typically resolves spontaneously by 3-6 months. Can do passive stretching exercises.
What is the most common associated condition with calcaneovlagus foot?
What is the most common surgery needed?
Posteromedial tibial bowing.
Most have a LLD. Some will need a surgery to address the LLD.
What transcription factor has been associated with clubfoot?
PITX1
Critical for limb development.
What is the mechanism of botulinum toxin A?
Competitive inhibitor of presynaptic cholinergic receptors.
Finite lifetime, usually does not last longer than 2-3 months.
Helpful in dynamic contractures, little benefit in static contractures.
What is the mechanism of Baclofen?
Not clearly understood.
Thought to act as a GABA agonist.
Intra-thecal administration is preferred to avoid the cognitive impairment of oral administration.
Usually only used for wheelchair bound children with CP.
When are contracture releases or tendon transfers most commonly performed in children with CP?
3-5 years.
Have spasticity but also voluntary muscle control.
What disease occurs from a repeat mutation that leads to lack of the frataxin gene?
How is it inherited?
Friedreich’s Ataxia
Autosomal recessive
Frataxin is a mitochondrial protein involved in iron metabolism and oxidative stress.
Usually wheelchair bound by age 30. Die by age 50 from cardiopmyopathy.
What is the mutation that leads to Marfan Syndrome?
How is it inherited?
Fibrillin-1 (FBN1) gene
Autosomal dominant
Sporadic mutation can occur in up to 30%
What mutations are linked to Larsen’s Syndrome?
Filamin B for autosomal dominant
Carbohydrate sulfotransferase 3 deficiency for autosomal recessive.
What gene mutation leads to spinal muscular atrophy?
survival motor neuron gene (SMN)
Lack SMN-1 protein with severity of disease based on number of functional copies of SMN-II
SMN critical to RNA metabolism and is a mediator of apoptosis.
A telomeric gene deletion.
What does mutation in the androgen receptor gene on chromosome X lead to?
Spinobulbar muscular atrophy.
Trinucleotide CAG expansion.
What is the inheritance pattern of Duchenne Muscular Dystrophy?
X-linked recessive.
What are the orthopaedic manifestations of DMD?
Calf pseudohypertrophy
Scoliosis
Equinovarus foot deformity
Joint contractures.
What are the non-orthopaedic manifestations of DMD?
Cardiomyopathy
Static encephalopathy
How is Becker’s Muscular Dystrophy Similar to Duchenne’s?
How does it differ?
Sex-linked, calf pseudohypertrophy, and CPK is elevated.
Dystrophin protein is decreased instead of absent, Later onset with slower progression. More prone to cadiomyopathy.
Average ate at diagnosis of BMD is 8 years
Average age at diagnosis with DMD is 2 years.
What is the prognosis of Duchenne’s?
Most unable to ambulate independently by age 10
Most are wheelchair bound by age 15
Most die of cardiorespiratory problems by age 20
What is a gower’s sign?
In DMD a child rises by walking hands up legs to compensate for gluteus maximus and quadriceps weakness.
What Lab is markedly elevated in DMD?
How much?
CPK
10-200x normal
What will a muscle biopsy show in DMD?
connective tissue infiltration and foci of necrosis.
Absent dystrophin with staining.
What is the most common skeletal dysplasia?
Achondroplasia
What mutation leads to Achondroplasia?
What is the inheritance pattern?
G380 mutation of FGFR3 (fibroblast growth factor receptor 3, on chromosome 4P)
80% is a sporadic mutation then autosomal dominant.
Gain of function mutation that increases inhibition of chondrocyte proliferation in the proliferative zone of the physis
Results in defect in endochondral bone formation. It is a quantitative cartilage defect.
What zone of the physis is involved in Achondroplasia?
Proliferative zone.
What mutation is associated with multiple epiphyseal dysplasia?
What is the inheritance?
Most common and most severe is COMP gene.
Can also have COL9A1, COL9A2, COL9A3, Matrillin 3, and SLC26A2 (diastrophic dysplasia sulfate transporter gene.
Halp of patients with clinical diagnosis of MED do not have the typical genetic mutations.
Autosomal dominant most common. The SLC26A2 mutation is autosomal recessive. Will present with at least one of the following: Clubfoot, cleft palate, clinodactyly(abnormal curvature of the small finger).
What is the mutation and inheritance of diastrophic dysplasia?
DTDST gene (SLC26A2) on Chromosome 5
Encodes for a sulfate transporter protein.
Leads to undersulfation of cartilage proteoglycan.
What is the mutation that leads to cleidocranial dysplasia?
What is the inheritance pattern?
RUNX2/CBFA1 mutation-transcription factor which regulates osteoblastic differentiation
Autosomal dominant
What is the most common lysosomal enzyme malfunction syndrome?
Morquio syndrome
What is the pathophysiology of lysosomal storage disorders?
Incomplete gylcosaminoglycan breakdown products (mucopolysaccharides accumulating and causing dysfunction in various organs.
What are the CRTAP and LEPRE1 genes associated with?
Severe, lethal forms of OI not associated with primary structural defect of type I collagen.
What is the difference between the AD and AR forms of Osteogenesis Imperfecta?
AD forms (Types I and IV) are milder.
AR forms (Types II and III) are more severe
What is the result of COL 1A1 and COL 1A2 gene mutations?
Osteogenisis Imperfecta
Causes abnormal collagen corss-linking via a glycine substitution in the procollage molecule.
What is different about Type V, VI, and VII Osteogenesis Imperfecta?
They have abnormal bone on microscopy and similar phenotype but no Type I collage mutation.
What is the structure of Type I collagen?
Triple Helix structure- possible because of glycine at every 3rd amino acid residue.
Two alpha-1 chains coded by genes COL1A1
One alpha-2 chain coded by gene COL1A2
What will you see on histology slides for Osteogenesis Imperfecta?
Increased diameter of haversion canals and osteocyte lacunae
replicated cement lines
Increased number of osteoblasts and osteoclasts
decreased number of trabeculae
decreased cortical thickness.
What is the most common pattern of inheritance for osteopetrosis?
benign autosomal dominant.
Also malignant autosomal recessive and intermediate autosomal recessive forms.
May skip generations. 75% gene penetrance.
What is Albers-Schonderg disease?
autosomal dominant osteopetrosis Type II.
Anemia, pathologic fractures, and premature osteoarthritis.
What is a risk factor for having a child with down syndrome?
Advanced maternal age. 1 in 250 in mother > 35 years.
What genetic mutation is associated with Trisomy 21?
COL6A1 and COL6A2 which code for Type VI Collagen.
Component of skeletal muscle extracellular matrix
Contributes to generalized joint laxity.
What HLA markers are associated with JIA?
DR4 with polyarticular
DR8, DR5, and DR2. Associated with pauciarticular
What percent of JIA patients are RF seropositive?
<15%
What is the classical form of Ehler’s Danlos syndrome?
What mutation?
What inheritance pattern?
Type 1 and Type II
Hyperextensible skin, widened atrophic scars, and joint hypermobility.
COL5A1 or COL5A2 mutation. Type V collage
Autosomal dominant.
What factor is decreased or absent in Hemophilia A?
Factor VIII
What factor is decreased or absent in Hemophilia B?
Factor IX.
Less common for.
How is Hemophilia inherited?
X-linked recessive.
Typically affects males only.
Ther is a rare form with a autoimmune etiology with no genetic inheritence.
What is a Bethesda Assay used for?
Measures the amount of factor VIII or IX antibody in the blood
<5 BU = low levels
> 5 BU = high levels
What labs findings are seen in a patient with hemophilia?
PTT prolonged with PT normal
LFTs normal
What is the signifigance of IgG antibodies to clotting factor proteins being present in a patient with Hemophilia?
Inhibits the response of therapeutic factor replacement.
Present in 4-20% of patients
Relative contraindication fur surgery.
What factor levels would you watn in a hemophiliac patient with the following issues:
Acute hematomas?
Aute hemarthrosis and soft tissue surgery?
Skeletal surgery?
Increase levels to 30%
Increase levels to 40-50%
Increae levels to 100% for the first week following surgery and then maintian > 50% for the second week.
What is responsbile for the major source of nutrition to the physis?
Perichondrial artery.
Mutations in DMPK and CNBP gene are responsible for what disease process?
Myotonic dystrophy
A mutation of what gene leads to absence of the dystrophin protein?
What disease process does this lead to?
Xp21 Gene
Duchenne’s Muscular dystrophy
What is the percent chance of septic arthritis based on 0,1,2,3, or all 4 of Kocher’s Criteria?
.2%
3%
40%
- 1%
- 6%
Criteria are ability to bear weight, fever >101.3 or 38.5, WBC >12, and ESR >40
In what patients are capnocytophaga canimorsus infections seen?
Dog bites
Rare, but potentially fatal in splenectomy patients
Mortality rate of 30-60% in immunocompromised
Causes cellulitis, sepsis, endocarditis, meningitis, DIC, ARDS, and death.
What is the first line antibiotic for Pasteurella multocida?
Amoxicillin/clavulanic acid
Commercial name is Augmentin
What condition is associated with HLA-B8
DISH
What percent nerve elongation will diminish a nerve’s microcirculation?
What percent will disrupt axons?
8%
15%
What 25-hydroxy vitamin D level is considered to be deficient?
<20ng/ml
What secretes Stromelysin and plasmin?
Both are metalloproteinases that are secredted by chondrocytes and have degradative action against cartilage.
What role does sclerostin play in bone metabolism?
Inhibits the WNT pathway and leads to decreased bone mass.
What is the function of Peroxisome proliferator-activated receptor gamma (PPARG)
Regulator of mesenchymal progenitor cells that induces adipocyte formation.
Osteoarthritis and formation of osteophytes is thought to be mediated by the differentiation of quiescent chondrocytes through what signaling pathway?
Indian hedgehog (Ihh)
What medication works by binding to and enhancing the ability of antithrombin III?
Unfractionated heparin works by promoting the ability of antithrombin III to inhibit factors IIa, III, and Xa.
Risks are bleeding and heparing induced thrombocytopenia (HIT).
The reversal agent is protamine sulfate.
What does the picture demonstrate?
The D-test.
This should be performed when erythromycin-resistant MRSA is identified as a pathogen and clindamycin is being considered as the antibiotic to be used.
Inducible clindamycin resistance can occur. It theh pathogen is an inducible strain a zone of inhibition in the shape of the letter D will occur. This is considered a positive test.
What is a CAMP test?
Used to identify group B Beta-hemolytic streptococci
What is an Etest?
used to determine the MIC(minimum inhibitory concentration and whether or not a specific strain of bacteriurm is susceptible to the action of a specific antibiotic.
what disease is associated with a mutation in the GNAS gene?
Fibrous dysplasia
What is Metabolic Syndrome?
Collectio of medical comorbidities that are known to be risk fractors for developing cardiovascular disease.
Increased risk of knee pain and OA with these patients.
Includes: Central obesity, dyslipidemia, HTN, and elevated fasting glucose levels.
What are the differences between Aging and Osteoarthritis in articular cartilage for categories listed in the image?
What does an increased adductor moment during gait lead to progression of what disease process within the limb?
Increased adductor moment during gait is associated with progression of knee osteoarthritis
Increased medial compartment pressures.
What are the four types of Gell-Coombs Reactions?
Type I- Allergic (Anaphylaxis)
Type II- Cytotoxic, antibody dependent. Ex Grave’s Disease or hemolytic anemia
Type III- Immune complex diseases such as serums ickness or SLE
Type IV- delayed type
What does Sclerostin do?
Direct antagonist of the WntB-catenin pathway and thus a key regulator of the formation of mineralized bone matrix and bone mass.
Anti sclerostin antiboides result in inactivation of sclerostin, therby promoting the anabolic Wnt/B-catenin pathway and resulting in increased bone density.
What factor stimulates differentiation and proliferation of myofibroblasts?
TGF-beta- leads to production of scar tissue.
Muscle regeneration occurs 7-10 days after injury. Facilitated by IGF-1, FGF, and NGF.
What is the function of tobramycin
It is an aminoglycoside.
Disrupts protein synthesis through irreversibly binding to 30S ribosomal subunit.
Leads to altered cell membrane permeability, disruption of the cell envelope, and eventual cell death.
What is the inheritance of amniotic band syndrome?
Sporadic
What is Anakinra used for?
What is its mechanism?
Disease-modifying antirheumatic drug.
Interleukin IL-1 receptor antagonist that blocks the binding of IL-1 to its cell membrane
Prevents this pro-inflammatory cascade.
What is the mechanism of tranexamic acid?
Antifibrinolytic that prevents the activation of plasmin from the inactive zymogen plasminogen.
Plasmin breaks down fibrin which is factor Ia.
Common X-Linked disorders include?
Hemophilia A
Duchenne muscular dystrophy
Becker’s muscular dystrophy
Hunter’s sundrome
Spondyloepiphyseal dysplasia (SED) tarda
What cellular structures are increased in bone cells relative to other cells?
Endoplasmic reticulum, Golgi apparatus, and mitochondira.
Allows for synthesis and secretion of bone matrix.
What is the most specific marker for osteoblasts?
Osteoclacin
What is Cbfa1(core binding factor alpha-1)/Runx2?
key transcription factor associated with osteoblast differentiation
What factors are involved in osteoblastic differentiation?
BMP- stimulates mesenchymal cells to become osteoprogenitor cells.
cbf alpha 1: RUNX2
Stable beta-catenin
PDGF
IDGF
What effect does estrogen have on bone production?
inhibits bone resorption and stimulates bone production by inhibiting adenyly cyclase.
What effect to glucocorticoids have on osteoblas bone production?
inhibit collage and bone matrix production.
What role does 1,25 dihydroxyvitamin D have in bone production.
Involved in osteoblast bone production.
Stimulates matrix and alkaline phosphatase synthesis
Production of bone specific proteins (Osteocalcin)
What do osteoblasts secrete than inhibits osteoclasts?
Osteoprotegrin (OPG)
OPG binds to RANKL on osteoblasts, preventing RANK activation
What activates the Jagged1-Notch pathway on osteoblasts?
What does this pathway regulate?
Parathyroid hormone
Hematopoietic stem cells
What is the origin of osteoclasts?
originate from myeloid hematopoietic cells from monocyte/macrophage cell lineage.
monocyte progenitors fuse together to form mature multinuclear cells. -> multinucleated giant cells
What is tartrate resistant acid phosphate?
Secreted by osteoclasts to lower the Ph (utilizing carbonic anhydrase) and increases the solubility of hydroxyapatite crystals
What role does Cathepsin K play in bone regulation?
major proteolytic enxyme that digests organic matrix at ruffled border.
In simple terms what is the mechanism of bisphosphonates?
Prevents osteoclasts from formin ruffled border and producing acid hydrolases
At what zone does the osteoclast attach to the bone matrix?
Sealing zone
Attach via integrins (avB3, a2B1, avB1) they are receptros for vitronectin that is found on the bone surface.
Arg-Gly-Asp (RGD) sequence allows extracellular bone proteins to bind directly to integrins.
What signaling factors activate osteoclasts?
Inhibit?
RANKL and IL-1
Calcitonin and IL-10
Is there a difference between mineralized bone matrix degradation and organic bone matrix degradation by osteoclasts?
Yes
Hydroxyapatite crystals dissolved by HCL secreted through ruffled border into resorption lacuna for Mineralized matrix.
Lysosomal cysteine proteinases, MMPs, and Cathepsin K for organic bone matrix degradation
What determines the function of osteoprogenitor cells?
Environment:
Low strain and high oxygen tension = osteoblasts
Intermediate strain and low oxygen tension = cartilage
High strain = fibrous tissue
What is responsible for tensile strength in bone?
Collagen
40% of bone is organic and 90% of that is Type I collage
triple helix composed of one alpha-2 and two alpha-1 chains.
What is responsible for the compressive strength of bone.
Proteoglycans (organic)
Composes of glycosaminoglycan-protein complexes.
Calcium hydroxyapatite (inorganic)
What is the inorganic component in bone?
Calcium hydroxyapatite (Ca10(PO4)6(OH)2- provides compressive strength
Osteocalcium phosphate brushite
What are the three main types of proteins involved in bone matrix?
Osteoclacin: Most abundant non-collagenous protein (10-20% of total). Produced by mature osteoblasts. Promotes mineralization and formation of bone. Marker of bone turnover. Can be measured in serum or urine.
Osteonectin: secreted by platelets and osteoblasts. Believed to have a role in regulating calcium or oganizing mineral in matrix.
Osteopontin: Cell binding protein
What is the blood supply to long bones?
Nutrient artery system
Metaphyseal-epiphyseal system
Periosteal system
Bone receives 5-10% of cardiac output
What system supplies the major blood supply to a long bone?
What about when it is immature?
Nutrient artery system.
Supplies the inner 2/3 of mature bone via the haversion system.
Immature bone recieves the majority from the periosteal system. Flow is centripetal (outside to inside)
How does direction of predominate blood flow differ within a bone for the following:
Arterial
Venous
Mature
Immature
Fracture
centrifugal (inside to outside)
Centripetal (outside to inside)
Centrifugal
Centripetal
Centripetal. Nutrient artery system is disrupted and periosteal system predominates.
What predominately stimulates osteoclast in a normal process?
Pathologic process?
RANKL
PTH (such as metastatic disease)
What is osteoprotegrin?
decoy receptor produced by osteoblasts and stromal cells that binds to and sequesters RANKL.
What molecules inhibit Osteoclasts?
Osteoprotegerin
Calcitonin
Estrogen- decrease in RANKL
TGF-beta
IL-10
What molecules stimulate bone resportion?
RANKL
PTH
IL-1- stimulates osteoclast differentiation
1,25 dihydroxy vitamin D
Prostaglandin E2- activates adenylyl cyclase and stimulates resorption
IL-6 (myeloma)
MIP-1A (myeloma)
When does peak mone mass occur?
What population has greater bone mass?
For the hip between ages 16 and 25.
Greater in men and African Americans.
What is the rate of bone loss after skeletal maturity in adults?
Women after menopause?
.3-.5% per year
2-3% per year for untreated woemn during the 6th-10th years after menopause
What are the dietary requirements for calcium:
Lactating women.
Pregnant women, postmenopausal women, and patients with a healing bone fracture.
Adolescents and young adults
Adults
Children
2000 mg/day
1500 mg/day
1300 mg/day
750 mg/day
600 mg/day
What is the mechanism of PTH in:
Bone?
Kidney?
Intestine?
Bone- Stimulates osteoblasts to secrete IL-6, IL-1, and other cytokines to activate osteoclasts and increase resorption of bone. Increases osteblast production of M-CSF and RANKL which increases number of osteoclasts. Osteoclasts do no express receptor for PTH.
Kidney- Stimulates enzymatic conversion of 25-OH-vitamin D3 to 1,25-(OH)2-vitamin D3 (active hormone form) which: increases resoprtion of Ca++ in kidney (increasing serum Ca++). Increases excretion of PO4- from kidney (decreasing serum phosphate)
Intestine- No direct action. Indirectly increase Ca++ absorption by activating 1,25-(OH)2-vitamin D3
What can recombinant calcitonin be used to treat?
Paget disease
Osteoporosis
Hypercalcemia
What kind of tumors secret calcitonin?
medullary thyroid tumors and multiple endocrine neoplasia type II tumors.
What is the origin and function of calcitonin?
Produced by clear cells in the parafollicles of the thyroid gland (C cells)
inhibit the number and activity of osteoclasts.
Osteoclasts have a receptor for calcitonin.
What has to happen before the ingested form of vitamin D is the active metabolite?
two hydroxylations in the liver and the kidney needed to form 1,25-(OH)2-vitamin D3
What is the function of Vitamin D in:
Liver
Kidney
Bone
Liver- activated vitamin D3 converted to 25-(OH)-vitamin D3
Kidney- 1,25-(OH)2-vitamin D3 (active hormone form) can be inactivated to 24,25-(OH)2-vitamin D3. This inactivity occurs with decreased levels of PTH or increased levels of serum Ca++,P.
Vitamin D parallels that of PTH by increasing reabsorption of Ca in the kidneys.
Bone- 1,25-(OH)2-vitamin D3 stimulates terminal differentiation of osteoclasts. Once they are mature osteoclasts vitamin D3 does not have an effect and they respond to cytokines released by osteoblasts.
1,25-(OH)2-vitamin D3 promotes the mineralization of osteoid matrix produced by osteoblasts
Peak bone mass attainement in both men and women is most dependent on what sex-steroid?
Estrogen
Therapeutic estrogen for women:
increases risk of?
decreases risk of?
Increases risk of heart disease and breast cancer
Decreases the risk of hip fracture and endometrial cancer(if combined with cyclic progestin)
Someone on therapeutic estrogen will have changes in what lab values?
Decrease in urinary pyridoline
Decrease in serum alkaline phosphatase
What function does thyroid hormone have bone formation?
Regulartes skeletal growth at the physis by stimulating:
Chondrocyte growth
type X collagen synthesis
Alkaline phosphatase activity
Thyroid hormoes such as therapeutinc thyroxine increase bone resorption and can lead to osteoporosis.
What effect does growth hormone have on the physis?
Effects the proliferative zone of the physis and in cases of oversecretion or increased response can lead to Gigantism.
What effect does growth hormone have on serium calcium?
Increased absorption in the intestine
Decreases urinary excretion
Function is interdependent with insulin, somatomedins, and growth factors (TGF-B, PDGF, mono/lyphokines)
What is the function of anabolic steroids on bone mass?
Increases bone loss by:
Decreasing Ca++ absorption in intestine through a decrease in binding proteins
Decreasing bone formation (cancellous more so than cortical bone) by decreasing collage synthesis and inhibiting osteoblast activity.
Limb bud development is under control of?
Fibroblast growth factor.
Enlargement of the limb bud is due to interaction between the apical ectodermal ridge and the mesodermal cells in the progress zone.
First identifiable by transvaginal ultrasound at 8 weeks.
What proteins are involved in chondrogenesis at sites of future joints during embryonic development?
WNT4
WNT14
growth and differentiation factor 5 (also known as cartilage-derived morphogenetic protein 1)
What is the difference in gain of funcion in FGFR2c affinity for FGF2 and Loss of function in FGFR2c specificity for FGF2?
Gain of function in FGFR2c affinity for FGF2 ->patients with severe craniofaacial features and mild hand syndactyly.
Loss of function in FGFR2c specificity for FGF2 leads to it being able to bind FGF10 which is expressed more in hands ->mild craniofacial featurs and severe hand syndactyly.
What signaling center and growth factor are involved in Proximodistal limb development?
Signaling center = Apical ectodermal ridge
Most important growth factor is FGF8
Issues in these areas will lead to proximal limb truncation such as radial absence or dysplasia. Can also lead to central deficiency such as a cleft hand.
What signaling center is needed for anteroposterior (radioulnar) limb growth?
Zone of polarizing activity- along posterior (ulnar) part of limb bud.
Signaling molecule Shh is critical.
Normal is high concentration on posterio (ulnar side) and low concentration on anterior (radial) side.
Abnormal upregulation of Shh in the ZPA can lead to polydactly
Downregulation leads to loss of ulnar digits.
Upregulation in the anterior side can lead to loss of thumb.
What role does HOX genes have in limb development?
Anterior-posterior (radioulnar) patterning together with Shh
Regulate somatization of the axial skeleton, essentially patterning digit formation.
What is the third signaling center invovled in limb development?
What does it control?
non-AER limb ectoderm/ Wnt signalling center (progress zone, PZ)
Dorsoventral axis.
Dorsal limb expresses WNT7a to regulate dorsal patterning. Responsible for dorsal features such as nails.
Ventral ectoderm expresses en-1 (engrailed-1 protein, antagonistic to WNT7a) allows ventral limb development.
What happens if there is a duplication of the zone of polarizing activity?
Mirror-image duplication of the limb.
The spinal column originates from what embryonic sturctures during development?
Paris of mesodermal sturctures known as somites
Develop in a cranial to caudal direction on either sife of the notochord and neural tube.
Process is dependent on the presence of the paraxis gene
Somite layers:
SCLEROTOME- layer will become the vertebral bodies and annulus fibrosus
MYOTOME- will lead to myoblasts
DERMATOME- becomes skin
What are the stages of secondary bone healing?
Inflammation
Repair
Remodeling
What is the source, receptor class, and function for the following growth factors?
Describe The Vitamin D Pathway
7-Dehydrocholesterol is stored in the skin where UV exposure converts it to previtamin D3
25-hydroxyvitamin D3:
When calcium is low, PTH levles become elevated which activates 1-alpha-hydroxylase in the kidney. This converts 25-hydroxyvitamin D to the active Vitamin D (calcitriol)
Laboratory level study of choice to determine Vitamin D deficiency.
Describe the PTH Pathway.
Function of PTH
Increase serum Ca++ and decrease serum phosphate in response to hypocalcemia/hypomagnesemia via:
Increased bone resorption of calcium and phosphate (bone is destroyed)
PTH receptor is on the osteoblasts which secretes IL-1 to activate osteoclasts
Increase kidney resorption of calcium in distal convoluted tubule
Decrease kidney resorption of phosphate
Increase 1,25-(OH)2 vitamin D production
Describe the composition of the sarcomere?
FILAMENTS: Thick myosin filaments and thin actin filaments.
BANDS: H band is myosin only
I band is actin olnly
Z line flanks each sarcomere and acts as site of attachment for actin filament
DURING MUSCLE CONTRACTION:
A ban stays the same length. I band reduces in length. H zone reduces in length.
Describe the difference between Type I and Type II muscle fibers
What is the most common through knee or above knee prosthesis for children?
Constant friction (single axis) knee.
Patients can walk on uneven terrain.
Not recommended for older or weaker patients.
Only allows a single speed of walking
What is Hysteresis?
Energy dissipation.
When tissue is loaded and unloaded, the unloading curve will not follow the loading cruve.
The difference between the two curves is the energy that is dissipated.
What is the difference on a stress strain curve between tendons and ligaments?
Tendons carry higher loads and recruit fibers quickly -> Smaller toe region.
Ligaments recruit fibers gradually -> elongated toe region.
Toe region- significant deformation for given load. In this region the crimped and relaxed fibers of the ligament straightened to take load.
What are the two types of ligament bone insertion?
Indirect (fibrous insertion)
Direct (fibrocartilaginous insertion)
What are the phases of ligament healing?
What are the layers of articular cartilage?
For the following factors how does age change them and how does osteoarthritis change them?
Descire the formation of collagen fibers?
Briefly describe the cell cycle?
Describe Types I, II, III, and IV immuological reactions.
For the following diseases what are the translocations and diseases involved?
For the following skeletal dysplasia what is the mutation?
What are the four categories of osteporosis risk factors?
Lifestyle
Medications
Genetic polymorphisms
Diseases
What are the two broad classifications of renal osteodystrophy?
What conditios does the radiographic findings suggest?
What are other radiographic findings?
Image is of a brown tumor that is found in patients with renal osteodystrophy.
Image below is of a looser’s zone
Will also see osteosclerosis from mineralization of osteomalacia bone.
Rugger jersey spine
Soft tissue calcifications
In children will see varus deformity of the femurs. Widened growth plate and zone of provisional calcification.
What will histology of renal osteodystrophy show?
Thinned trabeculae. See below.
Amyloid stains pink on Congo red stain.
Describe the different osteodystrophy conditions based on labs and their genetic inheritance?
What are the orthopaedic manifestations of Rickets?
Brittle bones with physeal cupping/widening
Bowing of long bones
Ligamentous laxity
Flattening of skull
Enlargement of costal cartilage (rachitic rosary)
Kyphosis (cat back)
Describe Vitamin D-resistant (familial hypophosphatemic) Rickets.
What are the three genetic forms.
What is Vitamin D-dependent Rickets?
For the following drugs specify when to stop and when to restart with regards to surgical procedures?
What is the diagnostic criteria for Rheumatoid arthritis.
What are the biologic, TNF anatagonist DMARDs?
Briefly descirbe Flexor tendon conditions in RA?
Describe Extensor Tendon Conditions in RA?
Describe the Extrinsic and Intrinsic coagulation cascades?
For the anticoagulants listed below describe their mechanism?
For the following medications list where in the coagulation cascade they exert their effect:
Unfractionated heparin
Lovenox
Warfarin
Fondaparinaux (Arixtra)
Rivaroxaban (Xarelto) and Apixiban (Eliquis). Same class less common Edoxaban (Savaysa or Lixiana)
Dabigatran (Pradaxa)
For the following disorders describe the changes in Serum Ca, Serum Phos, PTH, and the most common cause:
Hyperparathyroidism
Hypoparathyroidism
Ectopic PTH
Vit D Malabsorption
Hypo vit D with no phosphate excretion frim the kidney
What are the three classes of hyperparathyroidism?
What serum lab values are to be expected?
PRIMARY: hypersecretion of PTH by a parathyroid adenoma(90%)/hyperplasia(10%)
SECONDARY: Secondary parathyroid hyperplasia as compensation from hypocalcemia or hyperphosphatemia. Decreaed gut Ca++ absorption with increased phosphorus.
Associated conditions are chronic renal disease and renal osteodystrophy
TERTIARY: parathyroid gland becomes dysregulated after secondary hyperparathyroidism and secrete PTH regardless of Ca++ levels.
This image is consistent with what disease process?
hypophosphatasia
Image shows deossification of bone adjacent to growth plate.
Presentation is similar to Rickets. Genu varum and short stature.
Will also see abnormal dentition
No approved therapies or treatments.
What enzymes are targeted by NSAIDs?
What do these enzymes do?
COX-1 and COX-2
There are some COX-2 spefic inhibitors. Celebrex and Vioxx (rofecoxib). Maintains the beneficial effects of COX-1 (maintaining gastric mucosa, regulating renal blood flow, and influencing platelet aggregation). Also can be used in the perioperative period because they do not affect platelet function.
COX enzymes catalyze the formation of prostaglandins and thromboxane from arachidonic acid.
Describe the mechanism of the various classes of antibiotics?
what disease process is most likely depicted by the radiograph below?
This is a “White line of Frankl”
Seen in scurvy.
also will see bluish-purple hue of the gums with areas of hemorrhages.
Affects the spongiosa layer of the physis most.
What disease process is associated with altered BMP-4 signal transduction?
Fibrodysplasia ossificans progressiva
Also known as “stone man disease”
Massive spontaneous heterotopic bone so much that their bodies literally ossify.
What are the differences between VDDR type 1 and VDDR type 2?
VDDR (vitamin D-Dependent Rickets.
Type 1 is a deficiency of 1a-hydroxylase
Type 2 is caused by an inactivating mutation of the receptor for 1,25 (OH)2 vitamin D3.
