Vitamin D and Phosphorus

Question 1

What are the two types of bone?

Answer 1

Compact/cortical - 80%

cancellous/trabecular - 20%

Question 2

Osteoblast development

Answer 2

• Stem cell will be exposed to many signals and chemicals which will convert it to a pre-osteoblast
• With the right signals, it gets converted into a osteoblast
• It can get stuck in the bone and become an osteocyte. Also can become a lining cell

Question 3

Osteoblast has a common precursor with?

Answer 3

Adipocytes

Question 4

Bone cells

Answer 4

• Osteoprogenitor cells: Contribute to maintaining the osteoblast population and bone mass, from periosteum and bone marrow
• Osteoblasts: Synthesize the bone matrix on bone forming surfaces, from mesenchymal progenitor cells, uninucleated
• Osteocytes: Organized throughout the mineralized bone matrix, support bone structure and serve as mechanosensors, formed from osteoblasts, uninucleated
• 90% of the bone cells are osteocytes
• Lining cells: Line the surfaces of bone, quiescent osteoblasts, uninucleated
• Osteoclasts: Resorb the bone matrix, from hematopoietic / monocyte/macrophage precursor, multinucleated

Question 5

Which bone cell is the master controller of bone turnover?

Answer 5

Osteocytes. They sense the stress and force on bones. They have a half life of 25 years.

Question 6

Osteocytes

Answer 6

they are a series of fused cells (dendrites)

they communicate and regulate the bone building.

Question 7

What are key signals from osteocytes?

Answer 7

Sclerostin, DMP1, Phex, FGF23.

Question 8

Summary of Osteocytes

Answer 8

• Master regulator of skeletal activity
• Only permanent resident bone cell population
• During development changes from cuboidal cell to dendritic cell
• Most abundant cell in bone (90-95% of bone cells) – surface area 100 times greater than trabecular bone
• Integrates mechanical and chemical signals
• Sense stimuli and regulate effector cells (osteoblasts and osteoclasts
• Are coupled to the environment they inhabit
• Cell-cell contact via gap junctions
• Direct tethers to lacunae wall (proteoglycans)
• Play an endocrine role in controlling P homeostasis

Question 9

Timeline for remodeling bone?

Answer 9

28 weeks.

The building process is longer than the resorption.

Question 10

BMU Bone Modeling Unit (3 stages)

Answer 10

•Activation
o Rank and Rank L
o Pre-osteoclast expresses Rank (it is a receptor)
o Rank –L (from the osteoblast) binds to Rank to convert pre-osteoclast to osteoclast.
•Resorption
o Osteoclast causes the bone to break down.
o Osteoclasts die.
•Formation
o Osteoblast are activated.
o Osteoid is unmineralized bond.
o Some of the osteoblasts get stuck in the bone.
o Some get stuck on the lining.

Question 11

Difference between osteopetrosis and osteoporosis.

Answer 11

osteopetrosis - excess OB

osteoporosis - excess OC

Question 12

Fibrodysplasia Ossificans Progressiva

Answer 12

normal tissue or normal organ becomes another by destroying first tissue / organ and replacing it with another (phenotypic reassignment)

• Cells that should turn into muscle turn into bone

Question 13

What bone cells live the longest?

Answer 13

Osteocytes

Question 14

Hematopoietic precursor cells give rise to?

Answer 14

Osteoclast

Question 15

What is the decoy receptor to OB on macrophages?

Answer 15

OPG

Question 16

What is the most metabolically active bone tissue?

Answer 16

Spongy (trabecular)

Question 17

Calcium, P, and vitamin D interaction

Answer 17

when calcium is conserved, P is excreted. The P stimulates FGF23 to deal with PTH (look at diagram)

Question 18

Phosphorous

Answer 18

• Ubiquitous in body; DNA / RNA/ phospholipids / phosphorylation of many enzymes, proteins and sugars
• Integral component of ATP
• Integral component of bone

Question 19

Phosphorus homeostasis

Answer 19

• Goal to maintain serum calcium-phosphate product at level needed for mineralization of bone
• Too high – hyperphosphatemia
• Premature calcification of the vasculature
• Death due to cardiac events
• Too low – hypophosphatemia
• Muscle dysfunction / weakness
• Low cardiac output from respiratory muscle weakness
• Mental status changes / cell membrane instability (low ATP)

Question 20

P Absorption

Answer 20

• Absorption ranges 65-90% in infants and decreases to about 50-70% in adults
• Whereas calcium is about 30%
• Most occurs in small intestine by load-driven passive absorption
• Transcellular (through) or paracellular (around)
• Active absorption (in the enterocyte) via sodium-phosphorus cotransporters (NAPi-2b or NPT2B) and PiT1
• Calcitriol increases NaPi-2b cotransporters in intestine
• Can absorb P without D
• ***P absorbed with 70% efficiency – Ca absorbed with 30% efficiency – need separate mechanism to remove excess P released from PTH-mediated bone resorption

Question 21

Phosphorus – Urinary Excretion

Answer 21

• Major regulator of systemic P economy
• 95% reabsorbed in PCT (proximal convoluted tubule)
• Highly regulated in response to dietary P intakes
• NaPi-2a (NPT2A) and NAPi-2c (NPT2C) in kidney → key transporter
• Kidney responds to PTH, FGF23 and Pi concentrations

Question 22

Speculative Public Helath Link of Excess P

Answer 22

• FGF23 will inhibit PTH
• Decreased renal sytntehsis calcetriol
• Interfere with TG synthesis
• Plaque formation, heart attack, etc
• Insulin resistance → Type 2 diabetes
• Tumor promotion

Question 23

Hormones and regulation of Phosphorus

Answer 23

• 1,25(OH)2D – increase bone resorption (P release)
• PTH –
• Lowers renal P threshold = Plasma P concentration above which phosphate begins to appear in the urine
• Inhibits proximal tubular phosphate reabsorption
• Lowers serum P within MINUTES of giving hormone to humans
• FGF23 = Phosphatonin; A phosphatonin is a PTH-independent factor that regulates P metabolism
• FGF23, FGF7, secreted frizzled related protein-4 (sFRP-4), matrix extracellular phosphoglycoprotein (MEPE)
• Made from osteocytes

Question 24

FGF23

Answer 24

• Made by osteocytes; bone is an endocrine organ for regulation of P metabolism
• Binds to FGFR and Klotho
• Goal to rid excess P released into circulation from bone resorption
• Reduces P reabsorption by the kidney by withdrawing NaPi transporters on the apical membrane
• Reduces calcitriol (active vitamin D) production; indirectly reduces P absorption
• Might act on PTH grand to suppress PTH transcription

Question 25

High serum phosphorus

Answer 25

• Stimulate FGF23 production from OSTEOCYTE
• FGF23 suppresses renal 1-alpha hydroxylase; lower calcitriol (hormone that release Ca from bone and increase Ca absorption. It causes more reabsorption of P in kidney)
• Induces 24-hydroxylase gene
• Reduce intestinal absorption of P / Ca
• Increase renal phosphorus excretion (less NaPi cotransport)

Question 26

Low serum phosphorus

Answer 26

• Lower FGF23 production
• Stimulates 1-a hydroxylase production, more calcitriol
• Increase intestinal absorption of P
• Increase NaPi-2a (NPT2A) and NAPi-2c (NPT2C)

Question 27

Klotho

Answer 27

• Co-receptor for FGF23
• Calcitriol increases the production of FGF23
• Cyp23b1- 1-alpha hydroxylase
• Cyp24- 24,25 (OH)2 D
• So, the FGF23 inhibits 1alpha-hydroxylase

Question 28

FGF23 - summary

Answer 28

• Second pathway discovered for the regulation of Phosphate
• Fibroblast growth factor 23; FGF23
• Produced mainly by OSTEOCYTES
• Production stimulated by 1,25(OH)2D and PTH
• FGF23 inhibits 1-OHase, decreases 1,25(OH)2D production
• FGF23 increases urinary P excretion, (inhibit NaPi-2a / 2c)
• FGF23 decreases serum P
• FGF23 stimulates 24-OHase in kidney
• FGF23 suppresses PTH secretion; leading to calciuria
• Requires Klotho (glycoprotein that binds to FGF23 receptor (FGFR1cIII).
FGF23 production inhibited by
• PHEX: Phosphate regulating gene with homologies to endopeptidases on the X chromosome (produced by osteocytes)
• DMP1; dentin matrix protein 1; plays a role in mineralizing bone
• ENPP1