Grow taller by inhibiting CHOP?

Unfortunately, it seems that Hiroki Yokota is focusing more on Salubrinal than LSJL.  Salubrinal may have height increase applications and Salubrinal and Joint Loading have contrasting effects on EIF2alpha phosphorylation.  EIF2alpha phosphorylation is bad for height growth as it decreases protein synthesis.

Salubrinal also has effects on upregulating mRNA including CHOP.  Can CHOP help us grow taller?

Expression of CCAAT/enhancer-binding protein-beta (C/EBPbeta) and CHOP in the murine growth plate. Two possible key modulators of chondrocyte differentiation.

"CCAAT/enhancer-binding protein-beta (C/EBPbeta) and C/EBP-homologous protein (CHOP) [is expressed] in the growth plate. Proximal tibial epiphyseal growth plates from ten 15-day-old Wistar rats were used. Anti-proliferating cell nuclear antigen (PCNA), anti-5-bromo-2'-deoxyuridine (BrdU) immunostaining, terminal transferase dUTP nick end-labelling (TUNEL) and nucleolar organiser region-associated proteins (AgNOR) techniques were peformed. The normal growth plate showed that C/EBPbeta and CHOP factors are expressed both in the germinative/ upper proliferative and in the lower proliferative zones. BdrU+ and PCNA+ cells were present exclusively in the germinative and proliferative zones, while TUNEL+ and AgNOR+ cells were seen in all three zones of the growth plate. Acellular areas, hypocellularity, the increase in cell death and anomalies in the architecture of the cell columns were observed in the growth plates of C/EBPbeta (-/-) knockout mice. C/EBPbeta and CHOP transcription factors may be key modulators participating in the chondrocyte differentiation process in the growth plate."

"CHOP is a member of the C/EBP family, acting as a dominant-negative inhibitor of DNA binding."

"The growth plate of C/EBPβ(-/-) mice showed a decrease in the number of chondrocytes, disarray in chondrocyte columns, global hypocellularity and interspersed acellular areas"

"Without transcription factor Sox-9, cells committed to chondrocyte lineage [may be] unable to form pre-cartilaginous condensations and to activate a number of cartilage markers, including Col2a1 and aggrecan"<-so maybe you need to activate Sox9 for LSJL to work properly.

"CHOP is involved in programmed cell death and the induction of CHOP was evident in C/EBPβ(-/-) mice. CHOP contributes to the IL-1 growth-inhibitory signals through increasing production of IL-6, and IL-1 inhibits replication of cartilage cells and stimulates production of matrix metalloproteinases, among other actions"<-Thus maybe CHOP is bad for height growth and thus Salubrinal may be bad too.

Akt-1 mediates survival of chondrocytes from endoplasmic reticulum-induced stress.

"The unfolded protein response (UPR) is an evolutionary conserved adaptive mechanism that permits cells to react and adjust to conditions of endoplasmic reticulum (ER) stress. In addition to UPR, phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal regulated kinase (ERK) signaling pathways protect a variety of cells from ER stress. chondrocytes [are susceptible] to ER stress. Low concentration of thapsigargin (10 nM) reduced the viability of a chondrocyte cell line (N1511 cells) and that these cells were approximately 100 fold more susceptible to thapsigargin-induced stress than fibroblasts. In thapsigargin and tunicamycin-stressed chondrocytes induction of the proapoptotic transcription factor CHOP preceded that of the anti-apoptotic BiP by 12 h. Although both of these agents caused sustained Akt and ERK phosphorylation; inhibition of Akt phosphorylation sensitized chondrocytes to ER stress, while blocking ERK signaling by U0126 had no effect. Akt-1, but not Akt-2 or Akt-3, is predominantly expressed in N1511 chondrocytes. siRNA-mediated knockdown of Akt-1 sensitized chondrocytes to ER stress, which was associated with increased capsase-3 activity and decreased Bcl(XL) expression. Under condition of ER stress, multiple signaling processes regulate chondrocyte's survival-death decisions. Rapid upregulation of CHOP likely contributes to chondrocyte death, while Akt-1-mediated inactivation of caspase 3 and induction of BclXL promotes survival."

"Disruption of ER function interferes with protein folding and leads to the accumulation of unfolded proteins and the activation of an evolutionarily conserved adaptive response known as the unfolded protein response (UPR). If the UPR fails to counter the ER stress, caspase-mediated cell death ensues."

"Disruption of normal ER function is associated with dysfunction of the epiphyseal growth plate. In hypertrophic chondrocytes of transgenic mice expressing mutant collagen X, there is an accumulation of misfolded α1(X) chains and development of an UPR response"

"thapsigargin (inhibitor of sarcoplasmic and endoplasmic reticulum Ca2+ ATPases) causes a rapid initial release of Ca2+ from immature chondrocytes which returns to baseline levels after approximately 1 min."

"thapsigargin promotes a rapid phosphorylation of ERK that is sustained for 18 h."

Thus, Salubrinal may actually reduce height by increasing chondrocyte death.  LSJL does not upregulate CHOP in contrast to Salubrinal.  So Zhang and Yokota need to table Salubrinal research and go back to LSJL so we can all grow taller.

According to Knee Loading Stimulates Bone Formation in Tail-Suspended Mouse Hindlimb, LSJL increases Akt phosphorylation.  Loads were 1N at 5Hz for 5min.  Sample was taken one hour after loading, 5 days after initiation. Twice as much load as was used compared to the gene expression study. Although LSJL increases ERK1/2-phosphorylation which can cause apoptosis Akt-p spares cells from apoptosis.  Which may be why ERK1/2-p sometimes is pro-chondrogenic and sometimes not.  ERK1/2-p is both pro-chondrogenic genes and pro-apoptosis so Akt-p reduces the apoptosis resulting in a net chondrogenic effect

CHOP doesn't always cause apoptosis:

Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy.

"Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. ER stress [is important] in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1{up in LSJL} and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones.  ER stress and disrupted chondrocyte maturation [were present] throughout mutant [growth plate] hypertrophic zones. This disruption was defined by profiling the expression of wild type growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes."

"Activated Perk undergoes dimerization and trans-autophosphorylation, and is then able to phosphorylate the eukaryotic translation initiation factor 2-alpha (Eif2α), preventing formation of the translational initiation complex"

The unfolded protein response does affect hypertrophic chondrocytes:

Hypertrophic chondrocytes have a limited capacity to cope with increases in endoplasmic reticulum stress without triggering the unfolded protein response.

"Mutations causing metaphyseal chondrodysplasia type Schmid (MCDS) (e.g., Col10a1p.N617K) induce the pathology by a mechanism involving increased endoplasmic reticulum (ER) stress triggering an unfolded protein response (UPR) in hypertrophic chondrocytes. Here we correlate the expression of mutant protein with the onset of the UPR and disease pathology (hypertrophic zone [HZ] expansion) in MCDS and ColXTg(cog) mouse lines from E14.5 to E17.5. Embryos homozygous for the Col10a1p.N617K mutation displayed a delayed secretion of mutant collagen X accompanied by a UPR at E14.5, delayed ossification of the primary center at E15.5, and an expanded HZ at E17.5. Heterozygote embryos expressed mutant collagen X from E14.5 but exhibited no evidence of a UPR or an HZ expansion until after E17.5. Embryos positive for the ER stress-inducing ColXTg(cog) allele expressed Tg(cog) at E14.5, but the onset of the UPR was not apparent until E15.5 in homozygous and E17.5 in hemizygous embryos. Only homozygous embryos exhibited an HZ expansion at E17.5. The differential onset of the UPR and pathology, dependent on mutation type and gene dosage, indicates that hypertrophic chondrocytes have a latent capacity to deal with ER stress, which must be exceeded to trigger the UPR and HZ expansion."

The mutant mice experienced delayed recruitment of osteoclasts.

"the hypertrophic chondrocytes expressing mutant forms of collagen X experienced a profound UPR, a disrupted differentiation pattern including decreased expression of VEGF, and a decreased recruitment of osteoclasts to the VIF, causing an expansion of the hypertrophic zone."