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."