Microenvironmental regulation by fibrillin-1.
"Fibrillin-1 is a ubiquitous extracellular matrix molecule that sequesters latent growth factor complexes. Fibrillin-1 provides extracellular control of growth factor signaling. Mutations in FBN1 are mainly responsible for the Marfan syndrome (MFS), recognized by its pleiotropic clinical features including tall stature and arachnodactyly, aortic dilatation and dissection, and ectopia lentis. Each of the many different mutations in FBN1 known to cause MFS must lead to similar clinical features through common mechanisms, proceeding principally through the activation of TGFβ signaling[LSJL upregulates TGF-Beta expression]. Here we show that a novel FBN1 mutation in a family with Weill-Marchesani syndrome (WMS) causes thick skin, short stature, and brachydactyly when replicated in mice. WMS mice confirm that this mutation does not cause MFS. The mutation deletes three domains in fibrillin-1, abolishing a binding site utilized by ADAMTSLIKE-2, -3, -6, and papilin. Our results place these ADAMTSLIKE proteins in a molecular pathway involving fibrillin-1 and ADAMTS-10. Investigations of microfibril ultrastructure in WMS humans and mice demonstrate that modulation of the fibrillin microfibril scaffold can influence local tissue microenvironments and link fibrillin-1 function to skin homeostasis and the regulation of dermal collagen production. Hence, pathogenetic mechanisms caused by dysregulated WMS microenvironments diverge from Marfan pathogenetic mechanisms, which lead to broad activation of TGFβ signaling in multiple tissues[WMS causes short stature rather than tall stature and WMS messes where TGF-Beta signaling occurs(more in the skin and less in the cartilage for example) thereby linking TGF-Beta signaling to one of the reasons that people with Marfan's Syndrome grow taller]. We conclude that local tissue-specific microenvironments, affected in WMS, are maintained by a fibrillin-1 microfibril scaffold, modulated by ADAMTSLIKE proteins in concert with ADAMTS enzymes."
According to "A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression.", knockout of FBN1 can be lethal and no evidence of larger stature was shown. Thus, Fibrillin-1 is likely not a purely inhibitive compound on height growth and specific mutations must occur to increase height growth(numerous combinations of mutations work however).
It's possible that the malfunction of the fibroblasts due to the incorporation of truncated fibrillin-1 fibrils interferes with TGF-Beta signaling which results in height growth.
In the first study, we saw that also disorders in FBN1 can cause short stature. With the malfunctioning microfibril hypothesis in the last study, we can theorize that perhaps a specific truncation of fibrillin-1 results in short stature
What we can conclude is that microfibrils may play a role in height growth and that having less of them in the growth plate or possibly even the bone may be beneficial for height. Therefore, we might want to come up with ways to reduce the number of microfibrils(we need some though).
Immunolocalisation of fibrillin microfibrils in the calf metacarpal and vertebral growth plate.
"Overgrowth of limbs and spinal deformities are typical clinical manifestations of Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA){both diseases cause overgrowth}, caused by mutations of the genes encoding fibrillin-1 (FBN1) and fibrillin-2 (FBN2), respectively. FBN1 mutations are also associated with acromicric (AD) and geleophysic dysplasias (GD), and with Weill-Marchesani syndrome (WMS), which is characterised by short stature.Here we investigated the organisation of fibrillin microfibrils in the growth plate of the long bone and vertebra immunohistochemically. Fibrillin-1 was dual-immunostained with elastin, with fibrillin-2 or with collagen X. Fibrillin microfibrils are distributed throughout all regions of the growth plate, and that fibrillin-1 and fibrillin-2 were differentially organised. Fibrillin-1 was more abundant in the extracellular matrix of the resting and proliferative zones of the growth plate than in the hypertrophic zone. More fibrillin-2 was found in the calcified region than in the other regions. No elastin fibres were observed in either the proliferative or hypertrophic zones. This study indicates that, as fibrillin microfibrils are involved in growth factor binding and may play a mechanical role, they could be directly involved in regulating bone growth."
"Fibrillin microfibrils are associated with the elastic fibre network, which in general consists of an elastin core surrounded by a network of fibrillin microfibrils. An extensive elastic network is distributed in the ECM of many tissues"
"the network of microfibrils could play a functional role in the long bone and spinal growth. Microfibrils, as part of the elastic fibre system, are commonly thought to play a mechanical role"
Immunolocalisation of fibrillin microfibrils in the calf metacarpal and vertebral growth plate.
"Overgrowth of limbs and spinal deformities are typical clinical manifestations of Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA){both diseases cause overgrowth}, caused by mutations of the genes encoding fibrillin-1 (FBN1) and fibrillin-2 (FBN2), respectively. FBN1 mutations are also associated with acromicric (AD) and geleophysic dysplasias (GD), and with Weill-Marchesani syndrome (WMS), which is characterised by short stature.Here we investigated the organisation of fibrillin microfibrils in the growth plate of the long bone and vertebra immunohistochemically. Fibrillin-1 was dual-immunostained with elastin, with fibrillin-2 or with collagen X. Fibrillin microfibrils are distributed throughout all regions of the growth plate, and that fibrillin-1 and fibrillin-2 were differentially organised. Fibrillin-1 was more abundant in the extracellular matrix of the resting and proliferative zones of the growth plate than in the hypertrophic zone. More fibrillin-2 was found in the calcified region than in the other regions. No elastin fibres were observed in either the proliferative or hypertrophic zones. This study indicates that, as fibrillin microfibrils are involved in growth factor binding and may play a mechanical role, they could be directly involved in regulating bone growth."
"Fibrillin microfibrils are associated with the elastic fibre network, which in general consists of an elastin core surrounded by a network of fibrillin microfibrils. An extensive elastic network is distributed in the ECM of many tissues"
"the network of microfibrils could play a functional role in the long bone and spinal growth. Microfibrils, as part of the elastic fibre system, are commonly thought to play a mechanical role"
im going to read this one a couple times to wrap my head around it, many to terms and growth factors i never heard of before,
ReplyDeleteTyler, in one of your earlier posts this year you stated that being in a pool lowers hydrostatic pressure. Does the pressure bounce back to normal when you come out? Would you recommend swimming because it does increase GH secretion? You also stated that LSJL is optimized in 3 minute intervals for loading. Does this mean I should up my load time from 1 minute to 3 on each epiphysis?
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