Cells are embedded in ground substance

Osteoclasts = bone clearing = we are low in calcium

• DO NOT have PTH receptors

• they do have calcitonin receptors though

Osteoblasts = bone building = we are storing excess calcium

• HAVE PTH receptors

Total Calcium Concentration :

• All Forms = $2.2$$2.2$ to $2.6$$2.6$ milli-molar

• Ionized = $1.0$$1.0$ to $1.3$$1.3$ milli-molar

  • this is the form we care about

    • $C{a}^{2+}$$Ca^{2+}$ regulates PTH secretion

Cortical ( compact ) Bone = 80%

Trabecular ( spongy ) Bone = 20%

• where osteoblasts and osteoclasts live

How do Osteoclasts actually work ?

• they adhere tightly to surface of bone

• then after RANK and IL-6 binding ,

  • they secrete secrete $HCl$$HCl$ and acidic proteases into the lacuna via lysosomes

TRAP = mature osteoclast cell marker

• high amount = osteoclast is mature

Calcitonin = reduces osteoclast cleanup / bone re-absorption

• tones down the amount of calcium

Theres this other channel along the sealing zone , AN01

• if you block it , osteoclasts don't really clean anything up

  • less bone re-absorption

The whole bone re-absorption process takes about 2 weeks

The stop signal is given by Osteoprotegerin ( OPG )

• its a competitive decoy receptor for RANK-ligand

NF-𝜅B is a transcription factor that leads to a bunch of down stream protein products getting made

• one of which is TNF-𝛼

The main transcription factor that promotes osteoclast differentiation is NFAT

• you need calcium entry into the cell in order to activate NFAT

BAPTA-AM = calcium chelator = turns off NFAT signal ➡️ less RANK signaling ➡️ less osteoclast activity

Where does calcium come from ?

• is it from the cytosol ? or from the endoplasmic reticulum ?

If you knock out TRPv4 , then bone mass increases

• makes it plausible then that osteoclasts rely on TRPv4 channels

Side note , even if you knock out TRPv4 , you can still observe calcium "oscillations" in electrophysiology recordings

• proves calcium oscillations are not due to TRPv4 channels

As cells mature , they start to use TRPv4 channels more and more

• used then as a marker for osteoclast maturation

So again , where does this calcium come from thats generating these mysterious electrophysiology oscillations ?

Parathyroid glands have chief cells

• if they sense a reduction in extracellular calcium , they start secreting PTH

If they sense an increase in extracellular calcium , they inhibit the release of PTH

• but a weird thing happens , where the calcium-sensing receptor gets activated by extracellular calcium binding.

• then ➡️ $G_q$$G_q$ ➡️ PLC ➡️ PIP2 ➡️ PIP3 ➡️ causes ER to release calcium

• now we have excess calcium in the cytosol

• ok , but this normally is like the signal for a neuron to release synaptic vesicles

• however here , this high intracellular calcium leads to the INHIBITION of secretion of parathyroid hormone granules

Vitamin D causes the intestines to absorb more calcium

• leads to high extracellular calcium concentrations

• this then inhibits parathyroid chief cells from secreting PTH

• but specifically , Vitamin D causes an increase in the expression of TRPv5 , TRPv6 , calbindin , PMCA , and NCX

  • this is how calcium then is transported from the gut lumen , into endothelial cells