Research Article: Gene expression profiling suggests a pathological role of human bone marrow-derived mesenchymal stem cells in aging-related skeletal diseases

Date Published: July 28, 2011

Publisher: Impact Journals LLC

Author(s): Shih Sheng Jiang, Chung-Hsing Chen, Kuo-Yun Tseng, Fang-Yu Tsai, Ming Jen Wang, I-Shou Chang, Jiunn-Liang Lin, Shankung Lin.



Aging is associated with bone loss and degenerative joint diseases, in which the aging of bone marrow-derived mesenchymal stem cell (bmMSC) may play an important role. In this study, we analyzed the gene expression profiles of bmMSC from 14 donors between 36 and 74 years old, and obtained age-associated genes (in the background of osteoarthritis) and osteoarthritis-associated genes (in the background of old age). Pathway analysis of these genes suggests that alterations in glycobiology might play an important role in the aging of human bmMSC. On the other hand, antigen presentation and signaling of immune cells were the top pathways enriched by osteoarthritis-associated genes, suggesting that alteration in immunology of bmMSC might be involved in the pathogenesis of osteoarthritis. Most intriguingly, we found significant age-associated differential expression of HEXA, HEXB, CTSK, SULF1, ADAMTS5, SPP1, COL8A2, GPNMB, TNFAIP6, and RPL29; those genes have been implicated in the bone loss and the pathology of osteoporosis and osteoarthritis in aging. Collectively, our results suggest a pathological role of bmMSC in aging-related skeletal diseases, and suggest the possibility that alteration in the immunology of bmMSC might also play an important role in the etiology of adult-onset osteoarthritis.

Partial Text

Adult skeleton constantly undergoes bone remodeling to replace old/damaged bones by new bones, which is required for the maintenance of bone shape and strength of adult skeleton. However, bone mass decreases and bone fragility increases with age in both men and women. Although an increase in bone resorption rate associated with menopause is the primary cause of low bone mass in postmenopausal women, a decline in bone formation rate may also contribute to the loss of bone mass in both postmenopausal and age-related osteoporosis.

Aged bones are featured by decreased bone mass and increased fragility compared with young bones. Inadequate bone formation following excessive bone resorption is a major cause of age-related bone loss. Besides, aged skeleton is also commonly accompanied by inflammatory disease such as OA, as represented by the bone marrow donors in this study. Given that bmMSCs give rise to bone-forming cells, it is likely that the aging of bmMSC play an important role in the aging of skeleton, and may be even involved in the development of aging-associated skeletal diseases such as osteoporosis (OP) and OA. Unfortunately, molecular evidence that can support the above conjecture and link aging of bmMSC to OP/OA is still lacking. It is thus of great interest to understand the age-associated gene expression change to know the role of bmMSC in the pathogenesis of aging-related skeletal diseases. In this regard, we examined the transcriptome-wide changes of genes of bmMSCs derived from 14 donors of various age, and analyzed the array data by exploiting a multivariate linear regression model considering all known variables, i.e., age, presence of OA, and gender. This analytic platform allowed us to correct effects of the OA- and/or gender-related change of gene expression, to obtain a list of age-dependent genes (in the background of OA), and also a list of OA-associated genes (in the background of old age). As far as the age-associated genes are concerned, our data are in agreement with the results reported by Wagner et al. who demonstrated related effects of aging and replicative senescence on the gene expression profiles of human bmMSC/progenitors [11]. However, there is an overlap of only 8 genes between our and their data. These include the age-associated up-regulation of EPB41L3 and TCEAL7 involved in regulating cell proliferation; IL13RA2 involved in the signaling of transforming growth factor β1-mediated fibrosis; MFAP5 encoding a microfibrillar associated protein; ROBO1 involved in axon guidance; S100A4 encoding a calcium binding protein; STEAP3 involved in iron metabolism; and UBE2E2 involved in protein degradation. The little overlap might be due in part to the differences in the populations studied, cell culture conditions, array data processing, or analytical platform used. In addition to the above mentioned genes, we report novel findings about the age- and OA-associated changes in the gene expression profiles of bmMSC.





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