Robert Ballock and Cory Xian: Potential Height Increase Allies

Robert Ballock and Cory Xian are both studying growth plate regeneration.

I found this grant.

GROWTH PLATE REGENERATION

"Co-cultured chondrocytes and osteoblasts implanted into tibial bone defects in vivo [may] recapitulate the function of the normal growth plate and result in the reformation of columnar physeal architecture and resumption of longitudinal growth[our goal is to stimulate chondrogenesis with LSJL in the bone already]. [We will] determine the degree to which this optimized physeal construct replicates the function of the normal growth plate in vivo following implantation into a complete growth plate defect. Successful regeneration of growth plate cartilage architecture in vivo would have a transformational impact on the practice of pediatric orthopaedic surgery, providing not only the ability to replace growth plates irreversibly damaged by trauma, infection or irradiation, but also the possibility of restoring longitudinal growth in individuals beyond the age of skeletal maturity."

So this guy wants to help people grow taller.  Here's his profile.  Here's the highlights:

"key observations [include] the discovery that terminal differentiation of growth plate chondrocytes was a default pathway that could be accelerated by thyroid hormone, and that morphogenesis of columnar cartilage in the growth plate could be recapitulated in our serum-free three-dimensional pellet cultures by addition of thyroid hormone."<-so we have to explore thyroid hormone as a means of enhancing height growth more.

"We initially determined that the principal site of thyroid hormone action during skeletal maturation was regulation of the critical transition between cell proliferation and terminal hypertrophic differentiation in the growth plate.In addition to characterizing the expression of thyroid hormone receptors in this tissue, we also explored the interactions between thyroid hormone, vitamin D, and retinoic acid in regulating terminal differentiation of growth plate chondrocytes.  Other work established an important link between thyroid hormone-induced terminal differentiation and upregulation of cell cycle proteins p21cip-1, waf-1 and p57 kip-1, indicating that growth arrest at the G1-S restriction point of the cell cycle is an obligatory step in the terminal differentiation process of growth plate chondrocytes."

"These studies have demonstrated that peroxisome proliferator activated receptors (PPARs), which are upregulated in response to a high fat diet, are also expressed in growth plate chondrocytes and interfere with the normal transcriptional activation function of thyroid hormone receptors in these cells, eventually resulting in the inhibition of terminal differentiation and matrix mineralization that allows the subsequent mechanical failure of the growth plate to occur."<-This guy knows all the studies that have been highlighted on this blog.

He has $157,000 funding.  We should find out what he thinks about LSJL & growth plate regeneration.

Here's a Ballock study that seems related to the grant:

Leptin Antagonizes Peroxisome Proliferator-Activated Receptor-γ Signaling in Growth Plate Chondrocytes.

"Leptin is an obesity-associated cytokine-like hormone encoded by the ob gene.  Leptin promotes proliferation and differentiation of chondrocytes, suggesting a peripheral role of leptin in regulating growth plate function. Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcriptional regulator of adipogenesis. Locally, PPARγ negatively regulates chondrogenic differentiation and terminal differentiation in the growth plate. Leptin may suppress the inhibitory effects of PPARγ on growth plate chondrocytes. Chondrocytes were collected from distal femoral growth plates of newborn rats and were cultured in monolayer or cell pellets in the presence or absence of leptin and the PPARγ agonist ciglitazone. The results show that leptin attenuates the suppressive effects of PPARγ on chondrogenic differentiation and T3-mediated chondrocyte hypertrophy. Leptin treatment also leads to a mild downregulation of PPAR mRNA expression and a significant MAPK/ERK-dependent PPARγ phosphorylation at serine 112/82. Blocking MAPK/ERK function with PD98059 confirmed that leptin antagonizes PPARγ function in growth plate chondrocytes through the MAPK/ERK signaling pathway.  leptin signaling in growth plate cells is also negatively modulated by activation of PPARγ, implying that these two signaling pathways are mutually regulated in growth plate chondrocytes."

"Binding of leptin to its receptor triggers activation of janus kinases (JAKs), leading to phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3)"

"Suppressor of cytokine signaling 3 (SOCS3){upregulated by LSJL} protein acts as a feedback inhibitor of the JAK/STAT3 pathway, inhibiting STAT3 phosphorylation"

"results in disturbed columnar structure, decreased type X collagen expression{up in LSJL}, increased apoptosis, and premature mineralization in the growth plates"

"leptin synergizes with thyroid hormone in modulating terminal differentiation of growth plate chondrocytes"

"PPARgamma is expressed in growth plate chondrocytes, and activation of PPARgamma promotes adipogenic transdifferentiation of growth plate chondrocytes, while attenuating[represses] both chondrogenic differentiation and terminal differentiation "

"Incubating the growth plate chondrocytes with the PPARgamma agonist[activator] ciglitazone for 5 days decreased both Col2a1 and aggrecan mRNA expression"

"Coaddition of leptin reduced the ciglitazone-induced inhibition of these chondrogenic differentiation markers."  Leptin inhibited the PPARg increase in PPRE.

"leptin-induced increases in phosphorylated PPARg  were blocked by coincubation with the MAPK/ERK inhibitor PD98059, but not by the JNK inhibitor SP600125"

"Both MAPK/ERK and MAPK/JNK signaling can phosphorylate PPARg at a consensus MAPK phosphorylation site"

"leptin has been reported to increase phosphorylation of ERK1/2 in a time- and dose-dependent manner, but not phosphorylation of JNK"

And another study listed as being directly related to the grant:


Biodegradable photo-crosslinked alginate nanofibre scaffolds with tuneable physical properties, cell adhesivity and growth factor release.

"Nanofibrous scaffolds are of interest in tissue engineering due to their high surface area to volume ratio, interconnected pores, and architectural similarity to the native extracellular matrix. Our laboratory recently developed a biodegradable, photo-crosslinkable alginate biopolymer. The material [can] be electrospun into a nanofibrous matrix, and [can] enhance cell adhesion and proliferation on these matrices by covalent modification with cell adhesion peptides. Additionally, the potential of covalently incorporating heparin into the hydrogels during the photopolymerisation process to sustain the release of a heparin binding growth factor via affinity interactions was demonstrated. Electrospun photo-crosslinkable alginate nanofibrous scaffolds endowed with cell adhesion ligands and controlled delivery of growth factors may allow for improved regulation of cell behaviour for regenerative medicine."

"by covalently modifying the alginate with heparin,  FGF-2 was released in a sustained manner over the course of one week from these scaffolds, and the released growth factor retained its bioactivity as demonstrated by enhanced proliferation of HDFs[human dermal fibroblasts]"

Here's what another study had to say about growth plate regeneration(his email address: cory.xian@unisa.edu.au <-Search for papers by Xian CJ):

POTENTIALS AND CHALLENGES OF GROWTH PLATE REGENERATION USING EX VIVO EXPANDED MESENCHYMAL STEM CELLS OR MOBOLISING ENDOGENOUS PROGENITOR CELLS

We are trying to mobilize endogenous progenitor cells with LSJL.

"Recent studies using rabbit models to investigate the efficacy of bone marrow mesenchymal stem cells (MSC) to promote cartilage regeneration and prevent bone defects following growth plate injury have shown promise. However, translational studies in large animal models (such as lambs), which more closely resemble the human condition, are lacking.
Very recently, our labs have shown that ovine bone marrow MSC are multipotential and can form cartilage-like tissue when transplanted into mice. However, using a growth plate injury model in lambs, analogous to those described in the rabbit, autologous marrow MSC seeded into gelatine scaffold containing chondrogenic factor TGF-1{Maybe TGF-1 wasn't enough}, failed to promote growth plate regeneration. To date, no large animal studies have reported successful regeneration of injured growth plate cartilage using MSC highlighting the possibility that ex vivo expanded MSC may not represent a viable cellular therapy for growth plate injury repair. In addition, using a growth plate injury repair model in young rats, our studies have also focused on understanding mechanisms of the faulty repair and identifying potential targets for enhancing growth plate regeneration using endogenous progenitor cells. We have observed that bony repair of injured growth plate is preceded sequentially by inflammatory, fibrogenic, chondrogenic and osteogenic responses involving both intramembranous and endochondral ossification mechanisms. We have observed infiltration of mesenchymal progenitor cells into the injury site, some of which have the potential to differentiate to osteoblasts or chondrocytes and contribute to the bony repair of the injured growth plate.
This presentation will focus on our studies examining the efficacy of ex vivo expanded autologous MSC to enhance growth plate regeneration in the ovine model and work using a rat model aimed at identifying potential targets for enhancing cartilage regeneration by mobilising endogenous stromal progenitor cells."

Preclinical studies on mesenchymal stem cell-based therapy for growth plate cartilage injury repair.

"MSCs express adhesion molecules and can migrate to sites of injury healing"  CXCR4 and MCP3 are two proteins involved in MSC homing.

"some success [was observed] when allogeneic chondrocytes (collected from the growth plate) were delivered into the growth plate injury site of White New Zealand rabbits.  chondrocytes filled the defect and were able to form columns. In addition, although there were signs of endochondral ossification at the base of the injury site, no rejection of the implanted chondrocytes occurred"

"stimuli or signal molecules controlling their migration, proliferation (PDGF-BB, FGF-2{up in LSJL}), and chondrogenic differentiation (TGF-β1, IGF-I)."

"only a certain amount of gene expression was needed to induce chondrogenic differentiation of bone marrow-derived cells, and that overexpression by gene-induced transduction may have negative, opposing effect on chondrogenic differentiation"

"collagen family excluding collagen-V as well as adhesion proteins such as fibronection and vitronectin all influenced and encouraged the migratory and proliferatory behavior of MSCs"