RESUMEN
Understanding the mechanisms by which bone marrow mesenchymal stem cells (BMSCs) differentiate into bone-forming osteoblasts and marrow adipocytes is crucial to develop strategies for the treatment of several bone diseases. Age-related bone loss resulting in osteopenia and osteoporosis has been associated with reduced numbers of osteoblasts and increased numbers of adipocytes, likely originating from differentiation defects in BMSCs. Although many factors involved in the complex regulation of osteoblast and adipocyte cell lineages have previously been identified, their functional interactions in the context of BMSC differentiation and maintenance of bone homeostasis during ageing are unknown. Recent discoveries have provided important new insights into the mechanisms by which the nuclear envelope protein lamin A and vascular endothelial growth factor A (VEGF) mutually control BMSC fate. Particularly interesting is the finding that VEGF in this context functions as an intracellular protein, unaffected by neutralizing antibodies, and not as a secreted growth factor. These insights may not only facilitate the identification of new targets for treating bone diseases but also lead to improved design of tissue engineering approaches aimed at stimulating bone regeneration and repair.
Asunto(s)
Adipocitos/metabolismo , Adipogénesis , Envejecimiento , Lamina Tipo A/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Osteogénesis , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adipogénesis/genética , Envejecimiento/metabolismo , Envejecimiento/patología , Médula Ósea/metabolismo , Humanos , Osteogénesis/genética , Osteoporosis/metabolismo , Transducción de Señal/genética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
We present a detailed comparison of ectopic ossification (EO) found in tendons of biglycan (Bgn), fibromodulin (Fmod) single and double Bgn/Fmod-deficient (DKO) mice with aging. At 3 months, Fmod KO, Bgn KO and DKO displayed torn cruciate ligaments and EO in their quadriceps tendon, menisci and cruciate and patellar ligaments. The phenotype was the least severe in the Fmod KO, intermediate in the Bgn KO and the most severe in the DKO. This condition progressed with age in all three mouse strains and resulted in the development of large supernumerary sesmoid bones. To determine the role of exercise in the extent of EO, we subjected normal and DKO mice to a treadmill exercise 3 days a week for 4 weeks. In contrast to previous findings using more rigorous exercise regimes, the EO in moderately exercised DKO was decreased compared with unexercised DKO mice. Finally, DKO and Bgn KO mice tested using a rotarod showed a reduced ability to maintain their grip on a rotating cylinder compared with wild-type controls. In summary, we show (1) a detailed description of EO formed by Bgn, Fmod or combined depletion, (2) the role of exercise in modulating EO and (3) that Bgn and Fmod are critical in controlling motor function.