This treatment mostly looks applicable to those pre skeletal maturity but there is the possibility to inject new skeletal stem cells.
Stimulation of skeletal stem cells in the growth plate promotes linear bone growth
“skeletal stem cells were shown to be present in the epiphyseal growth plate (epiphyseal skeletal stem cells, epSSCs). Here, we explore the possibility that modulating the number of epSSCs can correct differences in leg length. First, we examined regulation of the number and activity of epSSCs by Hedgehog (Hh) signaling. Both systemic activation of Hh pathway with Smoothened agonist (SAG) and genetic activation of Hh pathway by Patched1 (Ptch1) ablation in Pthrp-creER Ptch1fl/fl tdTomato mice promoted proliferation of epSSCs and clonal enlargement. Transient intra-articular administration of SAG also elevated the number of epSSCs. When SAG-containing beads were implanted into the femoral secondary ossification center of 1 leg of rats, this leg was significantly longer 1 month later than the contralateral leg implanted with vehicle-containing beads, an effect that was even more pronounced 2 and 6 months after implantation. We conclude that Hh signaling activates growth plate epSSCs, which effectively leads to increased longitudinal growth of bones. This opens therapeutic possibilities for the treatment of differences in leg length.”
According to this paper Mechanotransduction pathways in the regulation of cartilage chondrocyte homoeostasis, “Mechanical stress up‐regulates Indian hedgehog expression (IHH) and activates hedgehog (Hh) signaling” “cyclic tensile strain activates Hh signaling and promotes the expression of ADAMTS‐5 in a primary cilia‐dependent manner, but in a high strain environment, histone deacetylase 6 (HDAC6) causes cilial disassembly and blocks this response”<-So we could potential mimic some of the effects of this study with mechanical loading because it also activates the hedgehog pathway but not too much activation as it blocks the mechanical loading benefits to hedgehog. So potentially with the right mechanical loading we could mimic the benefits of this study.
From the above picture, any method of increasing hedgehog signaling will work including potentially mechanical loading.
“Morphologically and functionally, the growth plate can be divided into the resting, proliferative, and hypertrophic zones. The resting zone contains slowly cycling cells, which, upon recruitment into the underlying proliferative zone, begin proliferating rapidly and arrange themselves into longitudinal columns of flat chondrocytes. Thereafter, these flat chondrocytes undergo further differentiation along with hypertrophy, forming the hypertrophic zone. Thereafter, the hypertrophic chondrocytes die or transdifferentiate, leaving a cartilaginous template on which spongy bone is built.”
“The resting zone contains a unique population of stem cells that express the parathyroid hormone–related protein (PTHrP). Furthermore, these stem cells reside in a niche that governs their abilities of renewal and generation of transit-amplifying proliferative chondrocytes. Interestingly, this niche arises postnatally, probably in association with maturation of the SOC, and only then can the stem cells obtain self-maintaining capacity and the ability to produce stable, long-lasting clones”
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The importance of the Hedgehog (Hh) signaling pathway in development of the skeleton is demonstrated by the observation that deletion of Indian hedgehog (Ihh) (normally expressed by prehypertrophic and hypertrophic chondrocytes), either globally or specifically in cartilage, virtually eliminates formation of the growth plate. Together with PTHrP, Ihh is involved in a negative-feedback loop that controls the rate of chondrocyte differentiation. More specifically, Ihh produced by prehypertrophic and hypertrophic chondrocytes diffuses to the resting zone, where it stimulates expression of PTHrP, which in turn inhibits the hypertrophic differentiation of chondrocytes.
In addition, if Hh signaling is inhibited either genetically within the growth plate or pharmacologically during postnatal growth, the growth plate fuses abruptly“<-can we manipulate hedgehog signaling to keep the growth plate open for longer?
” Hh signaling stimulates the proliferation and clonal activity of epSSCs independent of age.”<-this is very promising for being able to potentially get the skeletal stem cells and then stimulate Hh signaling in adults.
“Local temporal stimulation of Hh signaling lengthens the legs.”
You can see from F how dramatically Hedgehog signaling increased the growth plate(SAG).
“The bony epiphysis (which develops from the Secondary Ossification Center) appears to be an appropriate location for such intervention, allowing placement of the Hh pathway agonist in close proximity to the epSSCs.”
” In the experiments presented here, some compound is likely released into the bloodstream, since an increase not only in femoral length, where the SAG-containing beads were placed, but also in the tibia of the same leg was observed. The arterial blood flow in extremities goes in the proximo-distal direction, and it is plausible that some levels of SAG diffuse in the same direction as the blood flow.”<-therefore the compound could be put into the blood stream without the beads for overall height!
“Noriaki said he was surprised that the cells in the resting zone “weren’t just lazy and doing nothing, they’re very hardworking cells, they can occasionally wake up and keep making chondrocytes.””<-that is amazing that means that potentially they can form new growth plates.
“It’s been hypothesized for many years that chondrocytes at the bottom of the growth plate die, but these findings show definite evidence that they survive and continue to make bone, he said.”
Another study on this from Noriaki Ono:
A Subset of Chondrogenic Cells Provides Early Mesenchymal Progenitors in Growing Bones
“The hallmark of endochondral bone development is the presence of cartilaginous templates, in which osteoblasts and stromal cells are generated to form mineralized matrix and support bone marrow hematopoiesis. However, the ultimate source of these mesenchymal cells and the relationship between bone progenitors in fetal life and those in later life are unknown. Fate-mapping studies revealed that cells expressing cre-recombinases driven by the collagen II (Col2) promoter/enhancer and their descendants contributed to, in addition to chondrocytes, early perichondrial precursors prior to Runx2 expression and, subsequently, to a majority of osteoblasts, Cxcl12 (chemokine (C-X-C motif) ligand 12)-abundant stromal cells and bone marrow stromal/mesenchymal progenitor cells in postnatal life. Lineage-tracing experiments using a tamoxifen-inducible creER system further revealed that early postnatal cells marked by Col2-creER, as well as Sox9-creER and aggrecan (Acan)-creER, progressively contributed to multiple mesenchymal lineages and continued to provide descendants for over a year. These cells are distinct from adult mesenchymal progenitors and thus provide opportunities for regulating the explosive growth that occurs uniquely in growing mammals.”
Have to figure out what’s unique about these cells and if there is a way to make these cells reawaken
“Chondrocytes in the growth plate continue to proliferate well into adulthood in mice”
“ In the center of the developing cartilage mold, chondrocytes stop proliferating and become hypertrophic chondrocytes. These cells signal to induce the migration of mesenchymal cells into the marrow space; these cells then differentiate into osteoblasts that then form bone on top of the cartilaginous matrix. Perichondrial precursors expressing osterix (Osx) invade into the cartilage template along with blood vessels and eventually become both osteoblasts and stromal cells in the marrow space”
“growth-related mesenchymal progenitors identified here and adult mesenchymal precursors.” We have to get these back