28. Lab Investigation of Disorders of Calcium & Phosphate Metabolism

Question 1

RECAP: Describe the bone remodelling cycle.

Answer 1

Microdamage or mechanical stress stimulates the recruitment, differentiation and activation of osteoclasts that reabsorb the damaged bone.

Osteoclasts die by apoptosis, and osteoblasts migrate to the area of resorbed bone and replace it with unmineralised osteoid, which then becomes mineralised.

Question 2

RECAP: What components are important in the induction of osteoclasts differentiation by RANK ligand?

Answer 2

• RANK (receptor activator of nuclear factor kappa-B): surface receptor on pre-osteoclasts, stimulates osteoclast differentiation
• RANK-ligand: produced by pre-osteoblasts, osteoblasts and osteocytes; binds to RANK and stimulates osteoclast differentiation
• OPG (osteoprotogerin): decoy receptor produced by osteocytes; binds to RANK-L, preventing activation of RANK

Question 3

RECAP: Describe the Wnt signalling pathway

Answer 3

Wnt is a family of protein signalling molecules important in development throughout the animal kingdom. It is complex and highly conserved.

The receptor is called frizzled, which requires a co-receptor, Low-density lipoprotein receptor-related protein 5 (LRP5).

In adult animals wnt is involved in growth, differentiation and maintenance of many tissues, including bone. It is required for osteoblast differentiation

Wnt signalling is under negative control by various proteins, such as DKK (dickkopf) and sclerostin (SOST).

Question 4

RECAP: Describe the osteocyte regulation of bone remodelling (using the signalling pathway and ligands, etc)

Answer 4

Osteocytes express RANKL and macrophage-colony stimulating factor (M-CSF) to promote, and OPG and NO to inhibit, osteoclast formation and activity.

Osteocytes also regulate bone formation via the secretion of modulators of the Wnt signaling pathway.

PGE2, NO, and ATP act to activate Wnt signaling, whereas sclerostin, DKK1, and SFRP1 all inhibit Wnt signaling and subsequent osteoblast activity.

Maintenance of this balance between resorption and formation by the osteocyte is essential for bone homeostasis.

Question 5

Describe osteomalacia.

Answer 5

Bone mineralisation

Vitamin D deficiency: most common cause

Usually due to combination of low dietary intake and lack of exposure to sunlight

Elderly at risk, especially if in nursing home and not taking supplements

Breast-fed babies kept out of sunlight

Question 6

Describe vitamin D

Answer 6

Calcitriol (really a steroid hormone, not a vitamin!)

Synthesised in skin in response to exposure to UV (‘sunshine vitamin’)

Activated by 2 metabolic steps:

1) 25 hydroxylation in liver to form 25OH D3, major circulating metabolite
2) 1α hydroxylation of 25 OH D3 in kidney produces 1,25(OH)2 D3, or calcitriol, the active hormone

Question 7

How does renal phosphate reabsorption occur?

Answer 7

Occurs through a sodium-phosphate co-transporter; requires association with Na-H exchanger regulatory factor (NHERF) to work.

PTH causes the phosphorylation of NHERF, which causes it to endocytose, decreasing Na+ and HPO4 2- transport.