Bone and the Unfolded Protein Response: In Sickness and in Health

Abstract

Differentiation and optimal function of osteoblasts and osteoclasts are contingent on synthesis and maintenance of a healthy proteome. Impaired and/or altered secretory capacity of these skeletal cells is a primary driver of most skeletal diseases. The endoplasmic reticulum (ER) orchestrates the folding and maturation of membrane as well as secreted proteins at high rates within a calcium rich and oxidative organellar niche. Three ER membrane proteins monitor fidelity of protein processing in the ER and initiate an intricate signaling cascade known as the Unfolded Protein Response (UPR) to remediate accumulation of misfolded proteins in its lumen, a condition referred to as ER stress. The UPR aids in fine-tuning, expanding and/or modifying the cellular proteome, especially in specialized secretory cells, to match everchanging physiologic cues and metabolic demands. Sustained activation of the UPR due to chronic ER stress, however, is known to hasten cell death and drive pathophysiology of several diseases. A growing body of evidence suggests that ER stress and an aberrant UPR may contribute to poor skeletal health and the development of osteoporosis. Small molecule therapeutics that target distinct components of the UPR may therefore have implications for developing novel treatment modalities relevant to the skeleton. This review summarizes the complexity of UPR actions in bone cells in the context of skeletal physiology and osteoporotic bone loss, and highlights the need for future mechanistic studies to develop novel UPR therapeutics that mitigate adverse skeletal outcomes.

Keywords: ATF6; ER stress; IRE1; PERK; Protein misfolding; Proteostasis.

Fig. 1

Surveillance of protein processing by the UPR. (a) Secretory and membrane proteins co-translationally enter the ER and are acted upon by ER chaperones such as BiP. (b) Proteins that attain a functional conformation are trafficked via the Golgi processes (c) Misfolded proteins are directed for either proteasomal or lysosomal degradation via ERAD or autophagy, respectively. (d, e, f) PERK, IRE1 and ATF6 monitor protein processing and initiate the UPR in response to accumulation of misfolded proteins in the ER stress. (d) Upon stress, PERK oligomerizes and gets activated by autophosphorylation. Active PERK phosphorylates eIF2α and attenuates protein synthesis leading to selective translation of ATF4. ATF4 stimulates of amino acid synthesis, antioxidant genes, autophagy, and expression of Gadd34 and CHOP. GADD34 restores protein synthesis by reversing eIF2α phosphorylation. If ER stress persists, ATF4/ CHOP signaling triggers apoptotic program. (e) The RNase activity of the active IRE1 dimer splices XBP1 mRNA in response to ER stress. Spliced XBP1 (XBP1s) encodes a transcription factor that augments expression of ER chaperones and ERAD components. Degradation of ER targeted mRNAs by IRE (RIDD) reduces protein processing loads. Hyperactivated IRE1 can associate with TRAF2 and ASK proteins to initiate JNK and caspase mediated inflammation and apoptotic programs. RIDD mediated decay of TXNIP miRNA can lead to sterile inflammation and apoptosis. (f) ATF6, proteolytically activated upon translocation to the Golgi processes, release a bZIP transcription factor that induces expression of BiP, XBP1 and genes involved in ER proteostasis. The apoptotic outputs are highlighted in red. Figure created with Biorender.com