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."

What's the current status of Lateral Synovial Joint Loading research?

Since the publication of Lengthening of Mouse Hindlimbs with Joint Loading, there hasn't been papers directly related to LSJL likely due to CH Turner's death.  Are the scientists working on Lateral Joint Loading or do we have to rely on our own?

Here's what Stuart J. Warden's(wrote a paper related to LSJL and is CH Turner's mentee) working on:

NIH-NIAMS (R15 AR056858)
Long-term skeletal effects of exercise during growth
Role: Principal investigator (1.5 academic months)
$231,000

NIH-NIAMS (R01 AR052018)
The function of neurotransmitters in bone biology[should be interesting but not related to LSJL]
Role: Subcontract co-investigator (3 summer months) [PI-Bliziotes (Oregon Health and Science University)]
$1,480,725 (IU subcontract $608,000)

National Space Biomedical Research Institute (MA01604)
Extent, causes, and countermeasures of impaired fracture healing in hypogravity
Role: Subcontract principal investigator (1 academic month) [PI-Midura (Cleveland Clinic)]
$1,789,968 (IU subcontract $338,472)

Department of Defense
Secreted Wnt antagonists in disuse-induced osteoporosis
Role: Co-investigator (1 academic month) [PI-Robling (IU School of Medicine)]
$1,062,982

NIH-NICHD (R01 HD057126)
Supplemental vitamin D and functional outcomes in early adolescence[this should be very interesting given that the cyp27b1 enzyme related to Vitamin D[it converts Vitamin D to the active metabolite] has possible height shortening effects]
Role: Subcontract co-investigator (0.5 academic months) [PI-Lewis (University of Georgia)]
$1,076,127

Hiroki Yokota seems to still be working on it, in his research goals:  He states that his goals are:

"Analysis of molecular and cellular mechanisms in bone remodeling
Development of mechanical loading devices for strengthening bone[C-class clamps?]
Development of therapeutic agents for enhancing bone formation[chemical methods likely]"

Hiroki Yokota seems to be focused now on developing some sort of grow taller pill possibly:


"Hiroki Yokota, a professor of biomedical engineering at IUPUI developed a drug that stimulates bone growth. Normally a technology transfer might have occurred, but we were able to leverage a lot of resources through Indiana University (IU). Indiana Clinical and Translational Sciences Institute (CTSI) resources allowed us to hire a private contractor to create a new formulation that was better. Lilly scientists were invited to provide input on what they would do next. Kelley School of Business life sciences students helped develop a marketing plan that identified a potential market for broken bones in addition to osteoporosis. As a result, we hope to use this model to speed the process from the research bench to the bedside."<-this pill may upregulate TGF-Beta and may help people grow taller.  This is definitely part of his therapeutic agents.


Here's another article about it:  It's apparently a new compound.  Here's a paper discussing the drug:  Salibrunal activates genes involved in anabolic processes in bones <-these anabolic processes can play a role in helping you grow taller.  Salubrinal inhibits GADD34-PP1 phosphatase which can cause cell death.  The timeline for the drug estimates to be about 8 years.  Here's another article about Salubrinal.


"I was originally exploring mechanical stimulation, which is similar to exercise, to strengthen bones. But by studying these mechanisms, I came across a molecular pathway that became the beginning of this discovery."<-He discovered the pathways behind salubrinal while researching LSJL thus salubrinal may be related to the pathways involved in LSJL.


"Older populations are increasingly affected by weakened and broken bones as aging cells are no longer able to produce sufficient levels of collagen, the protein from which bones derive their strength. Salubrinal prevents this cellular decline by strengthening the body’s “protein-producing machinery,” which creates collagen and keeps bones strong."<-Type II collagen helps you grow taller so perhaps salubrinal could have height increase affects as well.


"the cells just enjoy the body’s rescue response without really experiencing any new negative pressure"<-So Salubrinal is anabolic.

Here's more about Salubrinal:


Salubrinal promotes healing of surgical wounds in rat femurs.


"Phosphorylation of eukaryotic initiation factor 2α (eIF2α), transiently activated by various cellular stresses, is known to alleviate stress-induced cellular damage. Here, we addressed a question: does elevation of eIF2α phosphorylation by salubrinal (a pharmacological inhibitor of eIF2α dephosphorylation) enhance healing of bone wounds? We hypothesized that salubrinal would accelerate a closure of surgically generated bone holes by modifying expression of stress-sensitive genes. To examine this hypothesis, we employed a rat wound model. Surgical wounds were generated on anterior and posterior femoral cortexes, and salubrinal was locally administered on the anterior side. The results showed that, compared to a contralateral control, the size of surgical wounds was reduced by 10.8 % (day 10) and 18.0 % (day 20) on the anterior side (both p < 0.001), and 4.1 % (day 10; p < 0.05) and 11.1 % (day 20; p < 0.001) on the posterior side. In addition, salubrinal locally elevated cortical thickness and increased BMD and BMC. Pharmacokinetic analysis revealed that subcutaneous injection of salubrinal transiently increased its concentration in plasma followed by a rapid decrease within 24 h, and its half-life in plasma was 1.2 h. Salubrinal altered the phosphorylation level of eIF2α as well as the mRNA levels of ATF3, ATF4, and CHOP, and suppressed cell death induced by stress to the endoplasmic reticulum. In summary, the results herein demonstrate that subcutaneous administration of salubrinal accelerates healing of surgically generated bone holes through the modulation of eIF2α phosphorylation."


<-we need to see if increasing mRNA levels of ATF3, ATF4, and CHOP will increase height.  This study suggested that joint loading reduced phosphorylation of EIF2alpha.  So Salubrinal does not operate in the same way as joint loading.  But joint loading increased mRNA levels of ATF3.  Individuals deficient in ATF4 show reduced height.  ATF3 is linked to chondrocyte development as suggested in the study.


"To alleviate cellular injury or initiate apoptotic cell death, cells induce an integrated stress response (ISR). During ISR, phosphorylation of the alpha subunit of eukaryotic initiation factor 2α (eIF2α) is activated, and this ISR-driven phosphorylation blocks an exchange process of eukaryotic translation initiation factor 2B from GDP-bound eIF2 to GTP-bound eIF2. Consequently, the global translation-initiation is suppressed except for a group of specific genes whose expression is presumably crucial for an adaptive response for survival. Thus, the modulation of a phosphorylated level of eIF2α potentially alters the fate of damaged tissues."<-so manipulating phosphorylation of EIF2alpha alters fate of damaged tissues so it may alter growth(there is always stress to cells even in healthy growth plates).  Note though that chondrocyte apoptosis may play a vital role in height growth.


"First, in response to 10 μM salubrinal, an increase in the phosphorylation level of eIF2α (eIF2α-p) was observed at 3 and 5 h. Second, this increase in eIF2α-p was dosage dependent for the administration of 10 and 50 μM salubrinal on days 1 and 2"

"The rationale for administration of salubrinal is that phosphorylation of eIF2α is cytoprotective during ISR, and salubrinal is used to protect cells from ISR and apoptosis"<-But again apoptosis may be important to growth plates.

"Using mice without bone wounds, that a salubrinal-treated femur had a higher BMD than a contralateral control femur and a vehicle control femur. These observations together with pharmacokinetic results indicated local effects of salubrinal, when applied subcutaneously. However, we also observed a gradual increase in body weight of the salubrinal-treated rats compared to vehicle controls, suggesting a possibility of a systemic side effect"<-could the increase in body weight be due to bone length?

The study: Reactive oxygen species and p38 MAPK regulate Bax translocation and calcium redistribution in salubrinal-induced apoptosis of EBV-transformed B cells states that salubrinal increased Ca2+ in B cells and Ca2+ uptake in mitochondria although this does not indicate that the same would occur in MSCs.  The general mechanism of action for salubrinal is described as "phosphorylated eIF2α-mediated survival has been known to lead to cap-dependent protein translation inhibition, activation of PI3K, induction of NF-kB, degradation of p53, and decreased load of nascent proteins in the ER, whereas phosphorylated eIF2α-mediated cell death has been known to decrease cyclin D1 translation and induce the ATF4-CHOP pathway"


He's in close proximity with Dr. Plopper who can help him with LSJL:

"Differentiation of human mesenchymal stem cells (hMSC) plated in/on defined ECM proteins: We are defining the effect of ECM contact on human mesenchymal stem cell differentiation. Our hypothesis is that contact with distinct ECM proteins stimulates specific signaling pathways that ultimately control the differentiation of these cells into bone-, cartilage-, or fat-producing cells."


This is key to us, as ECM proteins are one thing that are expressed during puberty but not post fusion(they can be induced though). Dr. Plopper even touches a course on ECM at Purdue.  Weeks 5-10 could help us grow taller, especially week 9 is about the ECM-cytoskeleton connection.

As could Dr. Kotha:


"Dr Kotha’s group studies the role of mechanical loading on damage and repair to bone at multiple length scales. They characterize how mineral and organic in bone support its deformation as load is applied. When this is combined with novel non-invasive ultrasound based technologies[Dr. Kotha could help us with LIPUS] being developed, the overall goal is to make devices that can be used to monitor the risk of bone failure at specific sites. They also evaluate how cells sense deformation of bone and what molecular pathways are activated in response to loading."


So maybe the reason why there haven't been LSJL studies lately is that Yokota, Kotha, and Plopper are working on something big.  If you want to go to the school of growing taller you should go to department of biomedical engineering at Rensselaer.


Here's what Ping Zhang is working on:

"Fabrication and application of unique loading devices."<-Again C-class clamp?

"Anatomical, physiological and mechanical characterization of bones and joints under mechanical loading[lateral joint loading].  Identification of cellular and molecular mechanisms involved in mechanotransduction of bone and joint cells."

Salubrinal

 Hiroki Yokota participated in this study.

Salubrinal Reduces Expression and Activity of MMP13 in Chondrocytes.

"Stress to the endoplasmic reticulum (ER) and inflammatory cytokines induce expression and activity of matrix metalloproteinase 13 (MMP13). Since a synthetic agent, salubrinal, is known to alleviate ER stress and attenuate nuclear factor kappa B (NFκB) signaling, we addressed a question whether upregulation of MMP13 by ER stress and cytokines is suppressed by administration of salubrinal.
Using C28/I2 human chondrocytes, we applied ER stress with tunicamycin and inflammatory distress with tumor necrosis factor α (TNFα) and interleukin 1β (IL1β). RNA interference with siRNA specific to NFκB p65 (RelA) was employed to examine a potential involvement of NFκB signaling in salubrinal's action in regulation of MMP13. We also employed primary human chondrocytes and evaluated MMP13 activity.
Tunicamycin activated p38 MAPK, while inflammatory cytokines activated p38 MAPK and NFκB. In both cases, salubrinal significantly reduced expression and activity of MMP13. Silencing NFκB reduced inflammatory cytokine-driven upregulation of MMP13 activity.
Salubrinal downregulates expression and activity MMP13 through p38 and NFκB signaling."

Now MMP13 is actually essentially for endochondral ossification.

"elevation of the level of phosphorylated eIF2a leads to expression of activating transcription factor 4 (ATF4)"<-salubrinal inhibits EIF2a dephosphorylation.

"In response to 10 ng/ml IL1b and 1 mg/ml tunicamycin, the mRNA levels of MMP1, MMP2{up}, and MMP14{up} were not altered, but the level of MMP3{up} mRNA was elevated"

"salubrinal decreased the level of p-IKK that was known to downregulate the NFkB inhibitor, IkB"

This study does present a clear linkage between Salubrinal and height but doesn't rule out increase applications.

"Tunicamycin is an inhibitor of N-linked glycosylation and the formation of N-glycosidic protein-carbohydrate linkages"

"Tunicamycin increased the level of eIF2a phosphorylation (p-eIF2a) at 1 h, followed by an elevation in the level of ATF4 at 3 h"

"Co-incubation with tunicamycin and salubrinal presented an increase in p-eIF2a and ATF4"

"Tunicamycin induced phosphorylation of p38 MAPK (p-p38 MAPK) at 1 and 2 h, while administration of 10 mM salubrinal suppressed the tunicamycin-induced increase in p-p38 MAPK"  Tunicaymin did not activate NFkB.

The following article is by the LSJL lab:

Effects of salubrinal on development of osteoclasts and osteoblasts from bone marrow-derived cells.

"Osteoporosis is a skeletal disease leading to an increased risk of bone fracture. Using a mouse osteoporosis model induced by administration of a receptor activator of nuclear factor kappa-B ligand (RANKL), salubrinal was recently reported as a potential therapeutic agent. To evaluate the role of salubrinal in cellular fates as well as migratory and adhesive functions of osteoclast/osteoblast precursors, we examined the development of primary bone marrow-derived cells in the presence and absence of salubrinal{so we can see any potential effects of BM-MSCs on salubrinal for LSJL}.
Using the RANKL-injected and control mice, bone marrow-derived cells were harvested. Osteoclastogenesis was induced by macrophage-colony stimulating factor and RANKL, while osteoblastogenesis was driven by dexamethasone, ascorbic acid, and beta-glycerophosphate.
Salubrinal suppressed the numbers of colony forming-unit (CFU)-granulocyte/macrophages and CFU-macrophages, as well as formation of mature osteoclasts in a dosage-dependent manner. Salubrinal also suppressed migration and adhesion of pre-osteoclasts and increased the number of CFU-osteoblasts. Salubrinal was more effective in exerting its effects in the cells isolated from the RANKL-injected mice than the control. Consistent with cellular fates and functions, salubrinal reduced the expression of nuclear factor of activated T cells c1 (NFATc1) as well as tartrate-resistant acid phosphatase.
Salubrinal exhibits significant inhibition of osteoclastogenesis as well as stimulation of osteoblastogenesis in bone marrow-derived cells, and its efficacy is enhanced in the cells harvested from the osteoporotic bone samples."

We need of Salubrinal's effects on MSC's pre-differentiation to see if it can have an impact on LSJL.

"Salubrinal is reported to attenuate molecular signaling mediated by nuclear factor kappa B (NFκB)"

"C57BL/6 female mice (7 weeks of age) were used"

"mRNA and  protein expression of NFATc1 is downregulated by salubrinal. NFATc1 is a member of the
NFAT transcription factor family and a master transcription factor for osteoclast development. NFATc1-deficient embryonic stem cells are unable to differentiate into osteoclasts"

"MafB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B), IRF8 (interferon regulatory factor 8), and Bcl6 (V cell lymphoma) have been mentioned as inhibitors of NFATc1"<-Salubrinal may act through these inhibitors and if it does in turn the effects of these inhibitors could have importance for LSJL.

The Protective Effects of Salubrinal on the Cartilage and Subchondral Bone of the Temporomandibular Joint under Various Compressive Mechanical Stimulations

"Excessive mechanical loads on the temporomandibular joint (TMJ) can cause mandibular cartilage degradation and subchondral bone erosion{so it's possible that salubrinal may have no impact on healthy bone}, but the treatment of these conditions remains challenging. Salubrinal, which target eukaryotic translation initiation factor 2 alpha, has been shown to have multiple beneficial effects on skeletal tissue. Here, we examined the effect of a Salubrinal injection on the mandibular cartilage and subchondral bone of the TMJ under various compressive stresses. We conducted in vivo analyses in rat models using various compressive stresses (40 g and 80 g), and we observed time-related degeneration and pathological changes in the cartilage and subchondral bone of the TMJ at days 1, 3 and 7 through histological measurements, subcellular observation, and changes in proliferation and apoptosis. After the Salubrinal injection, the thickness of the cartilage recovered, and the pathological change was alleviated. In the Salubrinal/light (Sal/light) compressive stress group, the drug altered the proliferation and apoptosis of chondrocytes most significantly at day 1. In the Salubrinal/heavy (Sal/heavy) compressive stress group, the drug increased the proliferation of chondrocytes most significantly at day 1 and reduced the apoptosis of chondrocytes most significantly at day 7. Salubrinal also increased the area of the bone trabeculae and suppressed inflammatory responses and pathological change in the subchondral bone of the TMJ. Together, these results indicate that the administration of Salubrinal reduces apoptosis and strengthens the proliferation of chondrocyte to varying degrees at days 1, 3 and 7 under various compressive mechanical stresses, both of which contribute to the recovery of cartilage thickness and the alleviation of pathological change. Salubrinal also suppresses inflammatory responses and pathological change in the subchondral bone of the TMJ."

Since salubrinal increased chondrocyte proliferation could it increase longitudinal bone growth?

"endoplasmic reticulum stress (ERS) regulates mechanical stress-induced cartilage thinning. Salubrinal, which is an inhibitor of ERS, can elevate the phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α). Through eIF2α-mediated transcriptional and translational regulation, Salubrinal has been shown to have multiple beneficial effects on skeletal tissue. First, Salubrinal downregulates the expression and activity of Matrix Metallopeptidase 13 (MMP13), in chondrocytes, suggesting its potential use for protecting chondrocytes and treating degenerative diseases, such as osteoarthritis. Second, the elevated phosphorylation of eIF2α induced by Salubrinal could stimulate osteoblastogenesis and bone formation. Third, Salubrinal suppresses osteoclastogenesis, followed by bone resorption and protection"<-Could any of these things make you taller?  I'd say there'd have to be a study with salubrinal on longitudinal bone growth.

" Compared to the controls, the mandibular cartilage of the light compressive mechanical stress group thinned gradually, and the thickness of the mandibular cartilage reduced to 85% (P<0.05), 70% (P<0.05), and less than 60% (P<0.01) of that of the control group in the 1-, 3-, and 7-day subgroups, respectively. Degeneration was observed. More lacunas were located in the proliferative zone (1-day subgroup of the light compressive mechanical stress group). The chondrocytes in the proliferative zone penetrated into the hypertrophic zones"

If the Loading plus Salubrinal groups have thicker articular cartilage regions that could indicate that salubrinal could help people grow taller.

Here's the effects of loading on the subchondral bone:

"The compressive stresses caused noticeable degenerative changes, including irregular changes to the order and morphology of the bone trabeculae and pathologic changes and inflammation in the heavy compressive stress group. Resorption of the trabeculae is indicated (arrow) in the 1-day and 3-day light compressive subgroups. Vacuole and inflammatory cells are indicated (arrow) in the 7-day compressive subgroup. After the Salubrinal injection, the trabeculae widths recovered. Vacuoles were not observed, and the trabeculae were continuous. In addition, inflammatory cells decreased."<-compressive stress without salubrinal may be more beneficial for inducing growth changes in the subchondral bone as degradation of bone is needed to induce height growth.

"In the heavy compressive mechanical stress group, the trabeculae resorbed extensively. The pathologic changes were most significant in the 7-day subgroup and took the form of fractures, vacuole and inflammatory cell infiltration. After the Salubrinal injection, the disorder of the bone trabeculae abated and recovered. Continuous trabeculae and alleviated inflammation could be observed. Fractures and vacuole disappeared."

Salubrinal reduced the number of apoptotic cells due to compressive loads.