Cell-specific response to mechanical stress and regulatory mechanism of differentiation : ligament/tendon cells versus osteoblasts

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Using PDL-L2, a ligament cell line established in our laboratory, we have demonstrated the followings:(1) Ligament cells have characteristics of osteoblastic cells at the early stage of osteoblast differentiation.(2) Ligament cells do not produce mineralized nodule in vitro in spite of expressing Runx2, a key transcription factor for osteoblast differentiation(3) This is due to suppression of Runx2 activity by homeobox protein Msx2.(4) Overexpression of Msx2 suppresses matrix mineralization by osteoblasts(5) Conversely, knockdown of Msx2 causes matrix mineralization by ligament cells(6) Mechanical stress accelerates and enhances matrix mineralization by osteoblasts, but without effect on ligament cells.(7) This is likely due to difference in integrins between these two cell types.Furthermore, we identified PIASxβ, first identified as an E3 ligase, as a key regulator for mineralization. The observations includes(8) For matrix mineralization, a transient increase of PIASxβ is required at an early stage of osteoblast differentiation and this is also required for mechanical stress-induced mineralization.(9) This effect of PIASxβ is sumoylation-dependent and through activation of osterix, another key transcription factor for osteoblast differentiation located at the immediate downstream of Runx2. Thus PIASxβ is a signaling molecule between Runx2 and osterix in osteoblast differentiation and mineralization.(10) Osterix promoter is auto-regulated by itself and this may play an important role in controlling matrix mineralization by osteoblasts.