Increased adipogenesis of osteoporotic human‐mesenchymal stem cells (MSCs) characterizes by impaired leptin action

Abstract

The bone marrow contains mesenchymal stem cells (MSCs) that differentiate to the osteogenic and adipogenic lineages. The fact that the decrease in bone volume of age-related osteoporosis is accompanied by an increase in marrow adipose tissue implies the importance that the adipogenic process may have in bone loss. We previously observed that MSCs from control and osteoporotic women showed differences in their capacity to differentiate into the osteogenic and adipogenic pathways. In vitro studies indicate that bone marrow stromal cells are responsive to leptin, which increases their proliferation, differentiation to osteoblasts, and the number of mineralized nodules, but inhibits their differentiation to adipocytes. The aim of the present report was to study the direct effect of leptin on control and osteoporotic MSCs analyzing whether the protective effect of leptin against osteoporosis could be expressed by inhibition of adipocyte differentiation. MSCs from control, and osteoporotic donors were subjected to adipogenic conditions, in the absence or in the presence of 62.5 nM leptin. The number of adipocytes, the content of PPARgamma protein, and mRNA, and leptin mRNA were measured by flow cytometry, Western blot, and RT-PCR, respectively. Results indicate that control and osteoporotic MSCs differ in their adipogenic potential as shown by expression of active PPARgamma protein. Leptin exerted an antiadipogenic effect only on control MSCs increasing the proportion of inactive phosphorylated PPARgamma protein. Finally, results obtained during adipogenesis of osteoporotic cells suggest that this process is abnormal not only because of increased adipocyte number, but because of impaired leptin cells response.

Osteogenic effects of D(+)β-3,4-dihydroxyphenyl lactic acid (salvianic acid A, SAA) on osteoblasts and bone marrow stromal cells of intact and prednisone-treated rats

“…Thus, statins may not be an osteogenic activator but rather an adipogenesis depressor, which may be attributed to their HMG-CoA inhibitory effect. Furthermore, recombinant leptin [34,35] , prostaglandins [36] and parathyroid hormone (PTH) [37] have recently shown significant osteogenic effects on MSCs. However, these hormones may lead to systemic side effects and are expensive.…”

The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis

“…However, the action of leptin on the bone appears to have both positive and negative consequences and is not fully understood. Several in vitro studies have confirmed the positive effects of leptin on osteoblast proliferation, differentiation, and suppression of osteoblast-dependent osteoclast recruitment, while negatively regulating adipogenesis via their receptors expressed on both lineages [109][110][111][112]. A number of studies in mice have indicated the negative influence of leptin on bone metabolism and function because of its ability to enhance the sympathetic output to bone from the hypothalamus [113].…”

Adipogénesis y osteoporosis

“…Se puede observar que la presencia de leptina durante dicha diferenciación, disminuye significativamente el contenido de PPARγ sólo en las c-MSCs (Figura 2A, C) 74 . Puesto que la expresión de mARN para PPARγ fue similar en ambos tipos de células, se podría conjeturar la participación de algún tipo de regulación postraduccional para dar cuenta del alto contenido de PPARγ de las o-MSCs.…”

“…Parece interesante, que la leptina agregada durante la adipogéne-sis aumentó significativamente el nivel de p-PPARγ sólo en las c-MSCs, lo cual es consistente con el efecto inhibitorio de leptina sobre la adipogénesis. En contraste, la presencia de la adipoquina durante la diferenciación adipogénica no cambió el nivel de p-PPARγ en las o-MSCs (Figura 2B y D) 74 . Se puede suponer que incluso cambios muy pequeños en la disponibilidad de PPARγ activo/inactivo afectaría el potencial adipogénico de las célu-las, debido a que ambos, mARN para PPARγ y la proteína tienen vida media corta 76 .…”

“…Además, leptina agregada exógenamente durante la adipogénesis de c-MSCs estimula la transcripción de este gen. En contraste, durante las etapas tempranas de la diferenciación adipogénica de o-MSCs, no se detecta el transcripto para leptina, a pesar de la mayor capacidad adipogénica de estas células. Sin embargo, la adición de leptina exógena durante la adipogénesis de las o-MSCs, determina la expresión del mARN para la adipoquina en forma tardía 74 , sugiriendo que estas células requieren altas dosis de leptina para desarrollar alguna respuesta. Se podría especular que la baja transcripción del gen para leptina en estas células resultaría de la actividad alta de PPARγ, ya que se ha demostrado en otro tipo de células, que una alta actividad de PPARγ inhibe la transcripción del gen de leptina 77,78 .…”