tut1 bio

BIOCHEMISTRY OF METABOLIC BONE DISEASE

1. Metabolic myopathies:
Definition:
1. Heterogeneous hereditary conditions.
2. Caused by specific enzymatic defects due to defective genes.
3. Affects muscle ability to maintain adequate energy & ATP → skeletal muscle dysfunction.
Example: glycogen storage diseases, Lipid storage disease.
Pathophysiology of MM:
A- MM presenting with exercise intolerance, cramps, and myoglobinuria.
Explanation Cramps and myalgia may occur after:
 Brief exercise:
Glycogen is the main source of energy during brief exercise,
so development of muscle cramps during brief exercise
indicates Glycogen storage diseases.
 Prolonged physical activity:
Free fatty acids are main source of energy during prolonged exercise,
so development of muscle cramps only after prolonged exercise and are worse during
fasting indicates lipid storage disease.
B- MM presenting with progressive muscle weakness due to deficiencies of de-branching
enzyme and carnitine.

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special types of MM:

Primary mitochondrial myopathy:
1. Genetic disorder of mitochondrial respiratory chain affecting SK MS.
2. Due to mutations in mitochondrial and nuclear DNA.
3. Exercise induces exercise intolerance + myalgia + muscle cramps.
4. Lack of energy production due to:
SK Ms mitochondrial dysfunction → appearance of exercise induced symptoms + ↑ lactate
production + phosphocreatine depletion.
Primary mitochondrial myopathy ‫ للفهم قراءة‬:
-Mitochondrial inheritance:
In this unique type of inheritance,
the mitochondria contain their own DNA.
-Only mitochondrial disorders caused by
mutations in the mitochondrial DNA
are exclusively inherited from mothers.
-If this is the way
a mitochondrial disease was inherited,
there is a 100% chance that each child in
the family will inherit a mitochondrial disease.
special types of MM :
a) Myopathic carnitine deficiency: b) Systemic carnitine deficiency:
Cause Impaired active carnitine transport Due to impaired hepatic
from plasma into muscle cells. biosynthesis and/or excessive renal
excretion of carnitine.

Level → ↓ carnitine level in muscles, but → ↓ Plasma, liver, and muscle

normal carnitine in plasma and
liver.
Clinically Clinically: it manifests during
childhood or early adult life as
progressive proximal muscle
weakness, exertional myalgia
Ms biopsy increased number of lipid droplets
carnitine levels.
Clinically: It manifests in infancy or
childhood as
1. Progressive muscle weakness
2. Sustained exercise or fasting →
Attacks of hepatic and cerebral
dysfunction.
markedly increased number of lipid
droplets

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2. metabolic bone disorder:

Bone Cells:
Common progenitor mesenchymal stem cells give:
-Osteoblasts:
produce and secrete α1 type-1 collagen and mineralize bone "Bone-forming cells
-Osteocytes:
a. make 95% of cells in adult skeleton.
b are embedded in mineralized bone.
c. secrete osteokines.
d. function as mechanical sensors.
-Marrow adipocytes.
Bone marrow macrophage gives:
-Osteoclasts "Bone resorbing cells".

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Bone Cell Energetic:

1. Osteoblasts:
- Utilize oxidative phosphorylation to:
a. Generate ATP.
b. Increase antioxidant enzymes production to combat effects of reactive oxygen species.
2. Osteocytes:
- Osteocytes are embedded in hypoxic environment, so depend on glycolysis.
3. Osteoclasts:
- Glycolysis is needed for its normal differentiation.
↑mitochondrial mass → ↑oxidative phosphorylation.
Bone Turnover Markers (BTM) :
Definition: Protein or protein derivative released during bone remodeling.
Example: C- and N-terminal telo-peptides of type-1 collagen are cleaved during bone resorption
and liberated in circulation at rate proportional to bone resorption activity.
Uses:
1. Diagnosis of fracture risk.
2. BTM respond rapidly to changes in bone physiology, so can be used to determine response to
therapies for osteoporosis.
Types:
a. Hereditary and acquired conditions: occurring secondary to disturbed bone metabolism.
b. May be primary affecting bone or secondary to:
- Nutritional deficiencies. - Chronic disorders. - Drug induced.
Clinically:
a. Causes non-traumatic fractures, bone pain and disability.
b. In pediatrics → reduced linear growth, bone deformations.
Important Metabolic bone diseases:
A- Rickets
• Rickets is an infantile bone disease.
• Etiology:
1. ↓ Ca, phosphorous and/or vitamin D in diet
2. ↓ Sunlight exposure → ↓ vitamin D synthesis.
• Manifestations:
1. ↓ Ca and phosphorus in bone cortex → Soft and deformed bone
2. Bowing of legs
3. Swelling in ankles and wrists.

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B- Osteogenesis imperfecta (Brittle bone disease):

• A bone disorder secondary to defect in genes of collagen synthesis.
• Clinically: A child born with soft bones.

C- Paget's disease:
• It is a chronic disease of the skeleton mostly affects old people.
• It mostly affects the spine, pelvis, long bones of the limbs, and skull.
• In healthy bone: remodeling removes old bone pieces and replaces them with new, fresh bone.
• In Paget’s disease: remodeling is out of balance → new bone that is abnormally shaped, weak,
and brittle.

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