Biochemistry - Shany and Osteoporosis - AbuShakra Flashcards
What is the pathway of formation of activated osteoblasts?
- Osteoblast mononuclear precursor cells (from stromal mesenchymal cells) –> proliferation –> differentiate –> mature osteoblasts
Secrete type I collagen for new bone formation
Once it forms a rigid matrix around itself it is trapped inside with fewer nutrients so it shrinks and becomes an osteocyte which has similar functions but to a smaller extent
What is the origin of formation of the osteoclast cells?
Begins from hematopoietic precursors in the bone marrow –> macrophages –> fusion of microphages to produce multinucleated osteoclasts –> polarization – ruffled membrane
Secrete acids, lysosomic enzymes, etc.
Integrin attaches osteoclast to bone matrix and in between them is the acid microenvironment (proteases, collagenase, acids all inside)
What are the ways that osteoblasts regulate osteoclast activity and differentiation?
- RANK
- RANK ligand produced and bound to osteoblast membrane
- Osteoclast progenitors have a RANK receptor (of the TNF family, activate signal transduction)
- RANK-ligand binds to RANK receptor and signals transduction and differentation of precursors into osteoclasts (fusion of membranes)
- PTH also communicates with RANK ligand on osteoblasts
- Also stays on active osteoclasts to regulate apoptosis and prolong life
- Indicates more resorption
- RANKL also produced by Th cells (important for RA mechanism) - Osteoprotegrin (OPG)
- produced by osteoblasts and secreted into the environment
- When OPG is high it increases binding to RANK ligand and blocks its binding to RANK receptor
- Can be measured in the blood
- Can cover ligand and block biological actions of active cells
- Mimicking drug: Denosumab (injected every 6 months IM)
- Increased OPG causes decreased bone resorption
What is the clinical presentation of Ehlers-Danlos Syndrome?
- Light Kyphosis
- A thin skin.
- Fingers characterized as spider type.
- A thin cornea ( eye )
Labs:
Hydroxylysine deficiency in collagen
Low activity of lysyl hydroxylase - very high Km with ascorbic acid
Normal prolyl hydroxylase
What is the structure of collagen?
Three polypeptide alpha-chains (tropocollagen)
Bound by disulfide bonds at the N- terminus
Glycine present every 3 AA (Gly-X-Y) to reduce bulk for twisting
H-bonds between 2 peptides of carboxyl and amino groups of alpha-chains
Covalent bonds between lysine and allysine residues within and between triple helices (made by lysin oxidase)
In each row tropocollagens are arranged head-to-tail staggered by 1/4 of their length to make a crystal-like structure (this is what causes mineral stain to stick)
What are the types of processing of AA on collagen and what is involved in these processes inside and outside the cell?
Hydroxylation
In the presence of vitamin C, oxygen, and alpha-ketoglutarate
1. Proline hydroxylase
2. Lysine hydroxylase (on lysine residue position 5)
Glycosylation of hydroxyl group
- UDP-Galactosyl Transferase
- UDP-Glucosyle Transferase
- Glucose added to galactose
Hydroxylation and glycosylation and inside the endoplastic reticulum, from there they go to the golgi
-Disulfide groups bond to form tropocollagen (3 alpha-chains)
Golgi exocytoses the tropocollagen and there they are cleaved
They line up in staggered rows
Covalent bonds form by deamination from lysine oxidase
What are the five major types of collagen?
I:
- has both genes expressed (alpha1)2+alpha2
- 90% of collagen
II and III:
All 3 are alpha chains
II is high carbohydrate (for cartilage, eye and intervertebral discs)
III is low carbohydrate (for blood vessels, skin, internal organs)
How does a DXA scan diagnose osteoporosis based on bone mass or density?
Measures levels compared to normal levels of young person = T-score
<1 SD under the average is normal
>1 SD but <2.5 SD is osteopenia
>2.5 SD is osteoporosis - treatment recommended
Z score is compared to a person of the same age
Risk of fracture is linearly to the T-score
What are bone biochemical markers in the serum and urine?
Serum:
Formation:
- Alkaline Phosphatase/ Bone specific alkaline phsophatase (BSAP):
- Indicates osteoblast activity because of the phosphate groups producing hydroxyapatite in the bone, but also found in the liver and other parts of the body (can get false positives)
- Carboxyterminal propeptide of type I collagen (PICP)
- Aminto-terminal propeptide of type I collagen (PINP)
Resorption:
- Cross- linked C-telopeptide of type I collagen (ICTP)
- Tartrate-resistant acid phosphatase (TRAP)
Urine:
- Hydroxyproline (found in collagen from the bone but also in other forms like meat in the diet)
- Free and total pyridinolines (Pyd- from all collagen)
- Free and total deoxypyridinolines (Dpd only from bone, most specific)
What is the bone composition and what is lost in osteoporosis?
70% inorganic minerals (hydroxyapatite) - directly lost in osteoporosis
22% Organic materials - mostly collagen and some extracellular material and other proteins- lost to structure loss as well
10% water
What is the cycle of remodeling in bone? How long is each stage and in total?
Total remodelling is 200 days
Formation is 150 days
Resorbing is much faster- 20 days
Reversal is between resorption and formation
What are trabecular bone and cortical bone and what is their % mass and turnover in the body?
What is their role in osteoporosis?
Trabecular bone is surrounded by cortical (compact) bone.
Trabecular bone is a larger proportion of the end of bones and in the spine and makes up 20% but has 3-10x faster turnover than cortical bone (80%) so more affected by osteoporosis
Cortical bone makes up 80% of mass but 20% of turnover. Makes up shafts of long bones and compact bones. Not involved in osteoporosis fractures.
What is the most common fracture in osteoporosis?
Vertebrae
