Endocrine Abstracts (2006) 11 S39

Hormonal regulation of mesenchymal stem cell differentiation in bone

Franz Jakob, Lothar Seefried, Norbert Schütze & Regina Ebert

Orthopedic Center for Musculoskeletal Research, Orthopedic Department, University of Würzburg, Germany.

Mesenchymal Stem Cells (MSC) are the source of regeneration of musculoskeletal tissues. Stem cells (SC) are rare and slowly dividing cells, situated in stem cell niches, regulated by non-stem-cell cap cells. Rare symmetric SC division regulates the SC pool. Asymmetric cell division gives rise to a transient amplifying pool (MSCTAP). The MSC niche is poorly characterized in contrast to MSCTAP and consecutive events of fate decision, commitment and secretion of chemotactic and angiogenic factors. MSCTAP can be isolated from bone marrow, bone chips, synovia, skin and other tissues. MSCTAP express steroid hormone receptors which are important in early fate decisions and differentiation like VDR, RAR, GR, TR, ER and PPARγ, the latter being involved in adipose tissue differentiation. GR, VDR and TR regulate factors important in endochondral ossification and chondrogenesis (e.g. dkk and CCN proteins). Estrogens produce proliferative effects on MSCTAP which may be mediated by so called non-genomic effects. Early MSCTAP express only low levels of ER but knockout leads to loss of mechanosensitivity of the osteogenic pathway of differentiation which may indicate some effects of ER in bone formation. Receptors for PTH/PTHrP are essentially involved in the regulation of early progenitors. It has been shown that they are important in constituting the hematopoetic stem cell niche rendering the osteoblast a cap cell for the hematopoetic niche. New hormonal factors which regulate renal phosphate metabolism and vitamin D activation as well as early fate decision of MSCTAP are the phosphatonins FGF 23 and sFRP4. Osteoblast-derived secreted FGF23 signals through FGFR expressed in MSCTAP and the kidney. Constitutively active FGFR mutants cause chondrodysplasia syndromes in humans indicating an important role in MSCTAP commitment. In summary MSC may be targets and tools for therapeutic strategies and their hormone receptor pattern provides molecular targets of great potential for osteogenesis and chondrogenesis.

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