The Endoplasmic Reticulum Stress and Disease Do You Know

The endoplasmic reticulum (ER) is a very important multi-functional organelle in

eukaryotic cells. While completing the basic physiological functions, the endoplasmic
reticulum becomes a pivotal platform for coordinated signal transduction with its
large membrane structure. The endoplasmic reticulum is a site for lipid and sterol
synthesis, maintenance of Ca2+ dynamic balance, protein synthesis and folding, and
post-translational modification, as well as lipid and steroid metabolism. The
endoplasmic reticulum cavity is a unique cell compartment capable of active
Ca2+ transport, which is the compartment with the highest intracellular
Ca2+ concentration.

Under normal physiological conditions, Ca2+ is absorbed into the lumen of the
endoplasmic reticulum by the cytoplasm through the calcium pump on the
endoplasmic reticulum membrane, and is released into the cytosol by the IP3R
and RyR channels, thereby maintaining the stability of free Ca2+ in the endoplasmic
reticulum. Due to its protein folding and transport function, the endoplasmic
reticulum has a large number of Ca2+-dependent molecular chaperones, such as
calcium reticulin and glucose-regulated protein 78. The endoplasmic reticulum must
strictly control Ca2 + levels to avoid Ca2+ imbalance leading to cell death. In
addition, the endoplasmic reticulum plasma membrane (PM) acts as a barrier to free
diffusion throughout the cell, connecting different organelles through a series of
contact sites.

A growing body of research indicates that ER-PM contact sites play an important role
in maintaining Ca2+ homeostasis, signaling, and lipid regulation. Genetic or
environmental damage can cause intracellular calcium homeostasis, oxidative stress,
nutrient deficiencies, glycosylation inhibition, and protein misfolding, thereby
disrupting endoplasmic reticulum function and inducing endoplasmic reticulum
stress. Endoplasmic reticulum stress lead to the protein incorrectly folded and
accumulated in the lumen of the endoplasmic reticulum.

The cells pass through a series of signal network transduction pathways

of PERK-eIF2α, IRE1–XBP1 and ATF6–CREBH to improve the correct folding ability of
the protein, inhibit the production and accumulation of proteins, and accelerate the
non-functionality and toxic protein degradation, triggering transcription of genes
involved in endoplasmic reticulum stress and enhancing the self-repairing capacity of
the endoplasmic reticulum. These reactions are collectively referred to as unfolded
protein response (UPR). If the endoplasmic reticulum stress is too strong or
persistent for too long, these reactions are not sufficient to restore endoplasmic
reticulum homeostasis, which ultimately leads to apoptosis.
Endoplasmic Reticulum Stress and Osteoporosis

Osteoporosis (OP) is a common systemic metabolic disease in the elderly. It is

characterized by bone pain, decreased bone strength, increased bone fragility, and
degeneration of bone tissue. Osteoporosis is marked by low bone mineral density
(BMD), which is associated with endoplasmic reticulum stress. The development of
the pancreas and skeletal muscle system after birth is required to pass the
PERK-eIf2α signaling pathway. PERK-eIF2α pathway can be activated by endoplasmic
reticulum stress. ATF4 is a downstream target molecule of the PERK pathway, and
ATF4 can stimulate cBFA1 to induce the expression of osteocalcin (OCN) in
osteoblasts. These results indicating that endoplasmic reticulum stress is closely
related to osteoporosis and bone development.