Pathology-Bone and Joint Flashcards
What determines when and where osteoblasts begin forming bone?
Osteoprogenitor cell location and growth factor stimulation governed by RUNX2/CBFA1 TFs and WNT/beta-catenin signaling pathway
What growth factors regulate osteoclast differentiation from monocytes?
The osteoclast precursor is stimulated by RANKL on an osteoblast or stromal cell. This activates NF-kB. M-CSF produced by osteoblasts bind M-CSF receptors on the osteoclast progenitor cells. This stimulate tyrosine kinase activity. Finally, WNT proteins from marrow stromal cells secrete WNT which binds LRP5/6 receptors on osteoblasts. This triggers beta-catenin and production of OPG…preventing osteoclast differentiation.
What ratio is a main control for bone resorption/formation?
RANKL : OPG
What can you test for in a patient’s serum that is very sensitive and specific for osteoblast activity?
Osteocalcin
What genetic mutations most often result in dysostoses (congenital bone malformations)?
Those in homeobox genes
What makes a midget?
Constitutive activation of FGF receptor 3 inhibits cartilage proliferation
What type of diseases result from over activation of LPR5? Under activation?
LPR5 stimulates the WNT/beta-cetenin pathway in osteoblasts. Overstimulation causes increased bone mass. Understimulation causes osteoporosis
What causes osteogenesis imperfecta?
Substitution of glycine residues in the collagen helix, mutating the alpha1 or alpha2 chains
What osteogenesis imperfecta types are on opposite ends of the disease spectrum?
Type 1 patients usually lead normal lives, type 2 usually dies in utero
Why do people typically have shorter stature when they have mucopolysaccharidoses?
The enzymes that degrade dermatan sulfate, heparan sulfate and keratan sulfate don’t work and accumulation of these proteoglycans damages chondrocytes and limits growth
A mother brings her 15 year old daughter in because of repeated bone fractures and recurrent infection. You take an x-ray of her forearm and get this image back. What pathological problem is causing this bone deformity?
This is osteopetrosis caused by a decrease in osteoclast activity. This decrease in activity can be due to change any variable that regulates osteoclasts (RANKL, M-CSF, OPG) or enzyme deficiency in carbonic anhydrase II. Limited osteoclast activity results in deposition of woven bone, which is weaker and can result in lots of breaks. Marrow is also replaced by spongiosa and immunity decreases.
What factors contribute to osteoporosis?
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A post-menopausal female comes to your clinic complaining of low back pain. Multiple vertebral bodies are tender to the touch and you suspect she has osteoporosis. What treatments do you prescribe?
1st make sure there isn’t a pathological fracture. Prescribe exercise, calcium, vitamin D and bisphosphonates (inhibit osteoclast activity)
A 70 year old male presents with bone pain, difficulty lifting his head and bowed legs. His bone biopsy is shown below. What is the pathogenesis of this disease?
This is Paget’s Disease. Note the mosaic pattern of lamellar bone. First there is an osteolytic phase with increased osteoclast activity. Then there is a mixed phase where osteoblasts are also highly active. Finally there is a sclerotic phase where the bone becomes coarse and thickened.
What kind of tumors is this person susceptible to?
This is someone with Paget’s Disease. They are at risk for giant-cell tumors, giant-cell reparative granulomas, extra-osseous masses of hematopoiesis and sarcoma.
What are the names of the childhood and adult diseases that can be caused by lack of vitamin D?
Rickets (children) and osteomalacia (adults). These disorders are a result of inadequately mineralized bone.
What combination of symptoms are the hallmark of this disease?
This is hyperparathyroidism (generalized osteitis fibrous cystica or von Recklinghausen disease of bone). Note osteoclasts boring through trabeculum and subperiosteal resorption. Increased bone cell activity, peritrabecular fibrosis, and cystic brown tumors are hallmarks of the disease.
What term is used to describe all skeletal changes due to chronic renal disease?
Renal osteodystrophy includes these conditions: (1) increased osteoclastic bone resorption mimicking osteitis fibrosa cystica, (2) delayed matrix mineralization (osteomalacia), (3) osteosclerosis, (4) growth retardation, and (5) osteoporosisRenal osteodystrophy includes
How do skeletal lesions from renal failure develop?
Renal failure => PHOSPHATE RETENTION => secondary hyperparathyroidism due to increased PTH secretion => increased osteoclast activity. Additionally, phosphate retention => inhibition of vitamin D conversion => reduced Ca2+ absorption. Finally, METABOLIC ACIDOSIS => bone resorption and release of calcium hyrdroxyapatite.
Why do people on dialysis have increased risk of loss of bone mineralization?
Aluminum gets into their system and inhibits deposition of calcium hydroxyapetite = osteomalacia
A patient comes to see you with a broken tibia from playing soccer the day before. He wants to know if you could splint it and let him play in next week’s game. Why can he not play in a week?
After a break, a hematoma forms around the bone as osteoclasts and osteoblasts are attracted by PDGF, TGF-beta and FGF. About one week after a fracture, the osteoblasts have laid a procallus, which is really only soft tissue and cannot tolerate weight bearing.
When can a bone typically tolerate weight bearing after a fracture?
Week 2-3. At this point osteoblasts have laid woven bone in the medullary cavity, chondroblasts have laid fibrocartilage and hyaline cartilage along the fracture line and the cartilage has been ossified to form the bony callus.
What process makes it difficult to tell where a bone was broken years after the break?
Weight-bearing forces promote bone remodeling and the bony callus is modified according to the force lines of the bone.
What complications arise during bone healing after a fracture?
Inadequate immobilization: normal callus does not form and can result in nonunion and synovial-like cells fill in to create a pseudoarthrosis. Infection is also a possible complication.
If you had to pick one part of your bone to become ischemic, which part would you pick?
Medulla. These infarcts go unnoticed where subchondral infarcts become progressively more painful and can cause severe secondary arthritis.
A patient comes to see you after having his vertebrae fused with pain in a vertebra two levels superior to the ones you operated on. The spinous processes are tender to the touch and the patient have a temperature of 38 C. What organism is most likely causing these symptoms? How do you treat this patient?
Staphylococcus aureus causes 80-90% of osteomyelitis cases. This patient needs an x-ray to confirm lytic bone damage followed by antibiotic therapy and possibly surgery.
Where are bacteria normally found in children with osteomyelitis infections? What about in adults?
Everywhere. The metaphyseal vessels connect the epiphysis to the metaphysis, providing a road for the bacteria to travel to all portions of the bone. In adults, they are localized to the epiphysis.
What happened to this dear femur?
Bacteria infected the bone caused the original cortex to necrose (sequestrum). Newly deposited bone is seen surrounding the sequestrum (involucrum).
A patient comes to see you with pain in her back when tying her shoes, localized tenderness to the spinous processes, fever, chills and weight loss. She has a history of HIV and physical exam reveals kyphotic deformities. Where did the organism causing these symptoms likely originate?
This woman is at risk for Tb because she has HIV. Her symptoms are consistent with Pott disease, which is Tb that moved from the lungs to the vertebral discs where it forms abscesses.
What is the difference between osteoid osteoma and osteoblastoma?
Osteoid osteomas are < 2cm, common in younger people, found in the appendicular skeletal cortex and nocturnal pain is relieved by aspirin. Osteoblastomas are > 2cm, found in the spine and unresponsive to aspirin.
A 19 year old male comes to see you due to a sudden fracture of the distal femur. Below is his radiograph. How do you treat this patient?
The image shows a Codman triangle where tumor cells penetrate the cortex and lift the periosteum. This is typical in osteosarcoma. These tumors have a high metastasis rate, especially to the lungs and must be treated with surgery and chemotherapy.
A teenage boy comes to see you after breaking his tibia playing football. His x-ray comes back and you have an additional finding. What do you expect histological examination of this finding to look like under a microscope?
This is a benign osteochondroma. You would expect to see disorganized cartilage growth as seen below because these tumors exhibit a cartilage cap.
A 25 year old female comes to see you because he thinks he broke his finger opening a jelly jar. His x-ray comes back and looks like this. If further analysis revealed multiple similar findings what condition may this patient have? How would you expect bone biopsy to look?
This is an endochondroma. Syndromes of multiple endochonromas are Ollier and Maffucci (Maffucci if the tumors are associated with soft-tissue hemangiomas). Bone biopsy would reveal nodules of hyaline cartilage encased by bone.
A patient comes to see you with a bony prominence coming from his iliac crest. You take a bone biopsy and the results are seen below. What is your diagnosis?
Chondroblastomas have a tendency to arise from epiphyses and apophyses (iliac crest). Note “chicken wire” appearance from mineralization surrounding chondroblasts.
A 20 year old male comes to see you complaining of dull, achy pain in his thigh. Findings in imaging studies show a lucent area surrounded by sclerotic bone. You’d o a bone biopsy and see this. What is your diagnosis?
Chondromyxoid Fibroma. Note stellate and spindle cells surrounded by myxoid mass of hyaline cartilage and fibrous tissue.
A 45 year old patient comes to see you complaining of a painful, progressively enlarging mass coming from one of his ribs. The tumor is excised and is viscous and gelatinous. Matrix also oozed from the cut surface. What largely determines if this tumor will metastasize or not?
This is a chondrosarcoma. They are common in the axial skeleton and metastasis rates go up as the tumor starts to break through the cortex.
This is a radiograph of a 4 year old girl you saw in your clinic. What cells are likely to be found in this lesion?
This is a non-ossifying fibroma of the distal tibia. Note eccentric lobulated radiolucency surrounded by sclerotic margins. Macrophages and fibroblasts will make up a large part of the cells in this tumor.
A teenage boy comes to your clinic with apparent craniofacial skeletal deformations. You take a bone biopsy of his mandible and see the results below. What is your diagnosis?
This is fibrous dysplasia. Note the woven bone trabeculae arising from fibrous tissue without osteoblasts. All of the normal components of bone are present, they are just not differentiated into their mature structures.
A 10 year old white male comes to see you with an enlarging mass on his thigh that is tender, warm and swollen. He also has a fever, elevated ESR and is slightly anemic. The patient’s bone biopsy is shown below. What is the molecular basis of this tumor formation and what would you expect to see on an x-ray?
This is Ewing sarcoma/PNET. Note round cells with scant cytoplasm and Homer-Wright rosettes. On x-ray you would expect to see a lytic tumor penetrating into the surrounding soft-tissue with reactive bone deposited in onion-skin fashion (bottom arrow).
A 30 year old patient comes to see you complaining of knee pain. On physical exam you note a mass prorating from the lateral portion of the knee. You take a bone biopsy and see this. What is causing the knee pain?
Giant-cell tumor/osteoclastoma. This is an expression of RANKL on monocytes that cause giant osteoclast-like cells to form. These tumors produce bulging soft-tissue mass with a thin shell of reactive bone.
A 22 year old female presents with pain and swelling in leg. Lab studies come back and look like this. What is your diagnosis?
Aneurysmal bone cyst. Note the blood-filled cystic space surrounded by fibroblasts, reactive woven bone and osteoclast-type giant cells.
What are the three stages of OA?
Chondrocyte injury => chondrocyte proliferation and inflammation of joint and subchondral bone => chondrocyte dropout and loss of cartilage due to repetitive injury
An overweight 32 year old male comes to see you complaining of hip pain. He says that it gets worse with use and is stiff in the morning. X-ray of his hip is shown below. What is your diagnosis?
Osteoarthritis. Note narrowed joint space, subchondral sclerosis, scattered cysts and osteophytes (arrows).
A patient comes to see you complaining that she cannot bend her fingers anymore. Physical examination reveals ankylosing of the joint. Bone biopsy is shown below. What led to ankylosing of the joints in this patient’s hand?
This is RA. Note inflammatory cells (mostly CD4+) infiltrating into the sub-synovial tissue. Eventually inflammation results in destruction of synovium and neutrophil infiltration. Osteoclasts are stimulated and subchondral bone is eroded and pannus forms. The pannus eventually causes fibrous ankylosis.
A patient comes to see you complaining of joint pain and firm, nontender papules on their skin. Biopsy of the skin lesion is shown below. What is your diagnosis?
RA. Note the area of necrosis surrounded by activated macrophages, lymphocytes and plasma cells.
A 45 year old male comes to see you with mild pain in his big toe. He says that he has a family history of gout. What gene contributes to this family history and why?
HGPRT. Free purine bases roam freely and form crystals if HGPRT is not salvaging them as it should. Crystals accumulate and activate neutrophils and macrophages which cause gout symptoms.
How long does it usually take for the pathognomonic hallmark of gout to appear?
The hallmark of gout are tophi. In most cases, it takes 20-30 years of MSU buildup to form tophi that will actually cause someone to become symptomatic.
A 30 year old female complains of knee pain, knee locking and recurrent swelling. Range of motion is poor in the joint and it feels stiff, firm and a nodule is palpable. The nodule is excised and is seen below. What contributes to the reddish color of the synovium?
This is a tenosynovial giant-cell tumor. These tumors have a high expression of CSF1 which attracts lots of macrophages. Macrophages (giant cells seen below) are hemosiderin laden which gives the tissue a reddish appearance.
