Thursday, November 15, 2012

LSJL gene expression versus trabecular bone

Skeletal site-related variation in human trabecular bone transcriptome and signaling.

"we have compared global gene expression profiles of human trabecular bone from two different skeletal sites that experience vastly different degrees of mechanical loading, namely biopsies from iliac crest and lumbar spinal lamina.
In the lumbar spine, compared to the iliac crest, the majority of the differentially expressed genes showed significantly increased levels of expression; 3406 transcripts were up- whilst 838 were down-regulated. Interestingly, all gene transcripts that have been recently demonstrated to be markers of osteocyte, as well as osteoblast and osteoclast-related genes, were markedly up-regulated in the spine. The transcriptome data is consistent with osteocyte numbers being almost identical at the two anatomical sites, but suggesting a relatively low osteocyte functional activity in the iliac crest. Similarly, osteoblast and osteoclast expression data suggested similar numbers of the cells, but presented with higher activity in the spine than iliac crest. "

The bone biopsy was from trabecular bone.

Genes upregulated in Spinal Lamina versus Iliac Crest(the spinal lamina should receive more loading than the iliac crest);
Col2a1{up in LSJL}
COMP
CILP
MYL1{up}
Pdlim3{up}
Clu
Nebulin{down}
Sox9{up}
Egr1{up}
MMP2{up}
BMP2{up}
Osteopontin{up}
BSP{up}
Cyr61{up}?
Acta2{up}?

Downregulated:
ITGA4{down}

Interesting to see the chondrogenic related Col2a1 and Sox9.

The supplementary data was confusing and I'm not sure which genes were actually upregulated but what's clear is that axial loading does induce chondrogenic genes which is consistent with our pathway analysis that chondroinduction may not be the failure of axial loading and it may be integration of those chondrocytes into a growth plate.

In this case possibly due to lack of Acan and other growth plate proteins.

Differential load-regulated global gene expression in mouse trabecular osteocytes.

"we have used a recently developed model whereby a single caudal mouse vertebra (C5) is subjected to controlled compression loading and further devised a method for the isolation of high quality RNA from trabecular osteocytes. RNA samples from loaded and sham-loaded individual vertebrae where then subjected to gene array analysis following the administration of a single or repetitive loading doses (thrice weekly for 4weeks). Focusing on extracellular genes potentially involved in mediating osteocyte-derived signals to the trabecular surface, we identified sets of genes differentially regulated by either single or multiple loading bouts as well as genes affected by both loading protocols. A comparison with published studies on load-regulated genes in cortical osteocytes revealed that the majority of these genes are specifically activated/silenced in the trabecular bone. Many of these genes could be clustered according to processes directly relevant to the life cycle and activity of osteoblasts and osteoclasts and their progenitors."

"nitric oxide (NO), prostaglandin E2 (PGE2), insulin-like growth factor (IGF-1), dentin matrix protein 1 (DMP-1) and sclerostin [are generated by osteocytes in response to mechanical loading]"

9 week old Female C57BL/6 mice.  All cells were removed other than osteocytes.

"Loading here was at 8 N, as this regimen generates peak strains of 880 με on the dorsal side and 820 με on the ventral side of C5"

Genes upregulated in trabecular osteocytes in response to single loading also up in LSJL:
Adamts4
Adamts1
Aspn
Chi3l3{down}
Olfm4{down}

Genes upregulated in trabecular osteocytes in response to repetitive loading also up in LSJL:
Ptn
Vcan
Aspn
Thbs4
Sema3c
Il33
Thbs2
MMP2
Cyr61
Ntn1
Sod3
Grem2

Down:
Metrnl
Chgb
Lefty2


A significant percentrage of genes were expressed in osteocytes that were also expressed due to Joint Loading and there were no deferentially expressed genes between the two studies.

A portion of LSJL Response is explained by mechanotransduction signals within osteocytes
The LSJL lengthening effect is not solely the result of osteocyte mechanotransduction as axial loading does not typically induce a lengthening response despite sharing many genes with lateral loading.

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