LEC 3: Extraskeletal Ossification
- Formation of cartilage and bone where they shouldn’t form
- Triggered by mech factors/trauma/inflamm
- Unphysiological diff of specific cells
- Skeleton-specific regulatory mechs as pot’l therapeutic targets
- Underlying conditions (e.g. mutations for FOP, POH; lifestyle for v.c.)
- Specific cells undergoing skeletal diff
- Location in body
- Specific outcomes: fatal in FOP; impairment in v.c.
a) Amorphous vascular calcification: mineral accum without cellular changes
b) Chondro-osseous vascular calcification: endochondral ossification of extraskeletal
cartilage/bone due to change in phenotype in soft tissues (e.g. SM and epith cells)
Clinical consequences: diastolic dysfunction, HT, ventricular hypertrophy, heart failure
Driven by abnormalities:
- Developmental: inappropriate re-establishment of developmental pathways
- Inflammatory: e.g. obesity is constant inflamm so can trigger cell changes
- Metabolic: poor nutrition, diabetes, excess/deficiency
If you KO MGP, v.c. occurs.
Initial sign is a bone abnormality in big toe.
Not much happens til trauma.
Fatal because heterotopic ossification interferes w lung func and muscles can’t support it.
Due to ACVR1 activating GoF mutation in IC domain, FGF receptor for BMP;
- Normally, ACVR1 threonine receptor binds to BMP, phosphorylates SMADs, which
forms heterodimers and then translocates to nucleus
- Mutated:ACVR1 binds to other ligands like activin as well
o Usually activin binds to type I and II receptor complex and acti