Week 3 Flashcards
Achondroplasia
Achondroplasia is caused by a point mutation in the FGFR3 (fibroblast growth factor receptor 3) gene resulting in replacement of the amino acid glycine by arginine (Gly380Arg). The normal function of FGFR3 is to inhibit chondrocyte proliferation. The gain-of-function mutation causes constitutive activation, which exaggerates the normal inhibitory effect. The result is early fusion of the growth plate, causing short stature.
Nutritional Rickets
- Nutritional bone disorder
- Vitamin D deficiency that leads to calcium deficiency
- Leads to poor mineralization of osteoid
- The growth plate thickens because the chondrocytes expand (disorganized growth) and because osteoblasts lay down osteoid ONLY (the matrix doesn’t become mineralized)
- Bone thickens from osteoid accumulation
Characteristics: distorted bone growth, weakened bone, thickening of bone around growth plate, epiphyseal widening from osteoid deposition, bowed legs (genu varum), growth plate fraying
Lab Findings: decreased calcium, decreased vitamin D, increased PTH, decreased phosphate, increased Alk Phos
Treatment: Vitamin D and calcium supplementation
Cleidocranial dysplasia
Total evidence diagnosis: supernumerary teeth in maxilla, anterior fontanelle is very large (look for it being open), poor formation or lack of formation of clavicle and scapula
Polymyalgia Rheumatica
- Process: disease of unclear etiology in people older than age 50 yrs, especially women; overlaps with giant cell arteritis
- Location: Muscles of the hip, shoulder girdle, and neck; symmetric
- Onset: Insidious or abrupt, even appearing overnight
- Progression and duration: Chronic but ultimately self-limiting
- Swelling: swelling and edema may present over dorsum of hands and feet
- TART: muscles often tender but not warm or red
- Stiffness: prominent, especially in the morning
- ROM: pain restricts movement, especially in shoulders
- Generalized symptoms: malaise, depression, weight loss, anorexia, and fever but no true weakness
Fibromyalgia Syndrome
- Process: Widespread musculoskeletal pain and tender points. Central pain sensitivity syndrome that may involve aberrant pain signaling and amplification
- Location: Multiple specific and symmetric “tender points,” often unrecognized until examined; especially in the neck, shoulders, hands, low back, and knees
- Pattern of spread: Shifts unpredictably or worsens in response to immobility, excessive use, or exposure to cold
- Onset: Variable
- Progression/Duration: Chronic, with “ups and downs”
- Swelling: None
- TART: Multiple specific and symmetric tender “trigger points,” often not recognized until the examination
- Stiffness: Present, especially in the morning—often confused with inflammatory conditions
- ROM: limitation of motion is absent, though stiffness is greater at the extremes of movement
- Generalized symptoms: Sleep disturbance, usually with fatigue on awakening; overlaps with depression and other pain syndromes
Steps in osteoclast resorption
○ Migration - podosomes, once they attach to surface they help with migration
○ Sealing/RB - actin ring attaches, and this creates a sealed zone; the ruffled border is inside that sealed zone
- Acidification: Needs to be in an acidic environment; comes from HCl and it is to degrade the mineral part of bone, demineralize hydroxyapatite, calcium and phosphate are released
○ Enzymatic Dissolution: Cathepsin K helps break down collagen (the enzymatic dissolution of the collagen)
Role of RUNX2 transcription factor in endochondral and intramembranous ossification
RUNX2, a transcription factor, promotes the differentiation of mesenchymal cells into osteoblasts during intramembranous ossification. In endochondral ossification, RUNX2 also promotes differentiation of mesenchymal cells of the perichondrium into osteoblasts. These cells deposit bone mineral that become the bone collar. RUNX2 also promotes chondrocyte hypertrophy within the growth plate and stimulates Indian hedgehog production, as part of the PTHrP-Ihh signaling axis.
Purpose of PTH
- To increase serum calcium levels; stimulates bone break down
- It increases RANKL expression –> increases osteoclast differentiation
- PTH –> GH –> IGF-1 (insulin growth factor)
- However, too much PTH is bad; creates too much IGF-1, which starts to promote osteoclast differentiation
Two ways it’s delivered:
- Catabolic - continuous exposure to PTH (it’s exactly the opposite of what we want)
- Intermittent/pulsatile - strongly anabolic, which increases amount of osteoblasts available and increases the rate at which remodeling is taking place (Remodeling is at a super high rate; turnover increases in a positive sense; there is increased resorption but it’s so far outpaced by increased formation of the PTH being intermittent and not continuous that it has a positive effect on bone; it decreases fracture risk by 40%)
What signaling protein functions to modulate osteoblast formation/differentiation?
Sclerostin - antagonist of wnt pathway; wnt –> B-catenin helps with cell proliferation and cell longevity (so sclerostin is going to inhibit this)
□Negative regulator of bone formation
□ The only cell to express sclerostin is the osteocyte
□ Expression of sclerostin is modulated by PTH and exercise (mechanical strain)/straining of substrate in lacunae and that strain leads to reduced sclerostin expression)
□ Higher strain/higher load, the less that osteocytes produce sclerostin
□ Low levels of sclerostin = high osteoblast proliferation and bone formation
High levels = low levels of osteoblast proliferation and bone formation
FRAX
A computer-based algorithm, the Fracture Risk Assessment Tool (FRAX) was developed by the WHO to calculate the 10-year probability of any major osteoporotic fracture (hip, spine, humerus, and wrist), separately of hip fracture, from clinical risk factors. This tool, though still not a perfect predictor, can help physicians decide whether to treat or simply follow an individual patient.
Explain how nutrient absorption in the gut is influenced by gut microbiota
Nutritional absorption in the gut is regulated to some degree by the gut microbiota. As mentioned previously, the contents of the gut microbiome can alter caloric intake at the gut endothelium, thereby changing the ratio of calories absorbed to the amount of food eaten.
- Alterations in caloric absorption are one way in which the gut flora can influence the development of obesity.
Alterations in the gut flora may also cause excessive inflammatory responses at the gut lining, which can impair the absorption of key nutrients. Additionally, the gut flora are the source of a number of key vitamins used by the body including cobalamin (B12), biotin(B7), folate, thiamine (B1), pyridoxal phosphate, pantothenic acid (B5), niacin (B3), vitamin K, and tetrahydrofolate.
What organs are involved in bone homeostasis?
Kidneys
Parathyroids
Intestines
Bone
What 3 principle hormones control calcium and phosphate serum concentrations?
- Parathyroid hormone
- Vitamin D2 and D3 (prohormone) and their metabolites
- Fibroblast growth factor 23 (FGF-23)
Effect of decreased estrogen on osteoporosis
Estrogen is an anti-resorptive hormone. Binding of estrogen with receptors on osteoblasts promotes osteoprotegerin expression. OPG is a negative regulator of osteoclast differentiation. In the absence of estrogen, osteoblasts and osteocytes express RANKL, which promotes osteoclast differentiation. More RANKL results in more bone resorption and osteoporosis.
Paget’s Disease
- Common in older patients
- Excessive bone remodeling/turnover
- Increased osteoclastic activity and body tries to compensate and produce more bone, but this bone isn’t quite sturdy and not well formed
- causes overgrowth of bone; the new bone is abnormally large, deformed
Clinical Features:
- Radiculopathy at spine, bone pain, bowing of legs, “chalkstick” fracture
Lab Findings:
- Increased bone Alkaline Phosphatase (reflects increases activity of osteoblasts)
Treatment: bisphosphonates and calcitonin
