TENDON-DEPENDENT CONTROL OF LONGITUDINAL BONE GROWTH
“Skeletal abnormalities caused by disproportioned bone overgrowth (LBO), are a common trait in Marfan syndrome (MFS), a connective tissue disease caused by mutations in the extracellular matrix (ECM) protein and TGFβ regulator fibrillin-1 (Fbn1). The cause of LBO in MFS is unknown and therapies are not available. Fibrillin-1 hypomorphic mouse model (Fbn1mgR/mgR) faithfully replicates MFS skeletal manifestations including elongated bones however, its early demise due aortic rupture limit the magnitude of LBO investigation.
To circumvent Fbn1mgR/mgR lethality and investigate the contribution of specific skeletal tissues to LBO, Fbn1 gene expression was targeted in developing limbs by crossing Fbn1Lox/Lox mice with Prx1-Cre, in or bone with Osx-Cre, in cartilage and perichondrium with Col2-Cre, in skeletal muscles with Mef2c-Cre, and ligaments and tendons with Scx-Cre. Bones length of Fbn1 conditional mice KO was measured and relevant histological, cellular and biomechanical parameters were assessed.
Fbn1Prx1−/+ and Fbn1Prx1−/− mice had longer limbs bones compared to WT mice and amount of fibrillin-1 in the limb matrix was inversely proportional to bone length. Interestingly, Fbn1 gene targeting in ligaments/tendons resulted in LBO, altered tissues’ mechanics and TGFβ-induced switch of tendon stem cells to chondrocytes. Gene targeting in other limb’s anatomical locations did not result in LBO thus ruling out the participation of surrounding tissues to this bone phenotype.
Fbn1 gene inactivation in ligament/tendon is associated with increased local TGFβ, altered biomechanical properties and LBO. As previously reported, ligaments/tendons respond to changes in mechanical load by increasing the levels and/or the activity of TGF-β while bones undergo morphological adaptation in response to muscle loads transmitted by tendons. We hypothesize that dysregulation of local TGFβ signaling and altered biomechanical properties of fibrillin-1 deficient ligaments/tendons affect endochondral ossification by improper load transmission to bone. By showing ligament/tendon-dependent regulation of postnatal longitudinal bone growth this study provides a paradigm-shift in tendon biology and it shades a new light on LBO pathophysiology in MFS, thus providing the bases for new pharmacological interventions for this and related skeletal conditions.”
So lower levels of Fbn1 means longer bone length and FBN1 deficient tendons and ligaments alter endochdondral ossification by altering load transmission to bone. We can alter load transmission without altering FBN1.
I recent did some LSJL measurements and I didn’t have any significant increase in length. I think the reason for this is that I wasn’t clamping long enough. During the last few months I’ve been clamping hard so that I stop clamping sooner due to pain and can get it over with. However, I don’t think that is enough time to build up hydrostatic pressure. This is contrast to the method I post recently that had a very long clamping time. I think that my attempt to shortcut the process by getting into more intense clamping faster denied me of results. Slower clamping also allows for the surrounding muscles and tendons to adapt to the clamping meaning an eventual more intense clamping force before they start resisting.
Given that mesenchymal stem cells can differentiate into chondrocytes via hydrostatic pressure it’s very likely that their is an epithelial intermediary to allow for chondrogenic differentiation and epithelial cells are important to form the resting zone of the growth plate. LSJL tries to increase hydrostatic pressure. Although response to hydrostatic pressure may be dependent on cell matrix interactions.
I do have strong faith in LSJL given wingspan increase results and possible finger length increase. I performed LSJL on my right finger. My right finger appeared longer than my left. I got X-rays and after exhaustive analysis all my left finger bones were in fact longer except for my right metacarpal. And upon observation most of my left hand bones do appear to be longer than my right. Thus, the difference in size between the right and left metacarpal is very likely due to LSJL.
So now I will be performing LSJL on my left index finger to try to get the left metacarpal longer than my right and I will be ramping up the clamping of other joints that I perform LSJL on more slowly and longer duration.
Update 12/10/2015: The Twitter Account of EpiBone actually wrote a response back to our tweet of its original reply. Technically, they did not confirm it. We corrected that error. My personal interpretation of what they said, if the reply is real, is that the representative from EpiBone said the theoretical tissue engineering is possible. We might have read too far into that message. They technically did not confirm my hypothesis. Semantics 🙂
Sometimes I have to give a lot of credit to the readers and this one goes to someone who actually did something. They contacted the people at EpiBone and asked a simple question.
What I proposed in previous posts about the research (and application) Dr. Warren Grayson and company was working on, and how it applies to making people with no growth plates taller, was I telling the truth?
Someone named BD wrote and got a reply. Like I said, it would take years. The answer is always “years into the future”. How many years? Me being an optimist, I say 20-25 years. However, biomedical research based companies who were started by Ph.D/Academics from universities are usually very cautious and slow. More likely, assuming the rate of technological growth, It would be another 40 years or so.