Mesenchymal stem cells from osteoporotic patients produce a type I collagen-deficient extracellular matrix favoring adipogenic differentiation

Abstract

Mesenchymal stem cells (MSCs), precursor cells resident in the bone marrow, have the capacity to differentiate into bone, cartilage, fat, and connective tissue. We have recently reported that MSCs from "healthy" donors differ from cells obtained from osteoporotic postmenopausal women in their proliferation rate, mitogenic response to osteogenic growth factors, and potential to mineralize. The purpose of this study was to examine the factors that explain the differential capacity of MSCs derived from "healthy" control and osteoporotic postmenopausal women to support mineralization. In addition, we examined the factors that regulate the differentiation of osteoporotic cells into adipocytes. For this purpose, we isolated MSCs from bone marrow of donors and analyzed the synthesis and deposition of type I collagen, the main component of bone extracellular matrix, the time course of gelatinolytic activity expression, the deposition of transforming growth factor beta (TGF-beta), and the ability of cells to differentiate into adipocytes. Our results indicate that cells derived from osteoporotic donors synthesized 50% less type I collagen than normal cells and maintained higher levels of gelatinolytic activity under differentiation conditions (70% versus 15% after 14 days in culture). MSCs derived from osteoporotic women produced 60-65% less TGF-beta and expressed higher adipogenic capacity. We conclude that the capacity of MSCs derived from osteoporotic postmenopausal women to generate and maintain type I collagen-rich extracellular matrix is decreased, favoring their adipogenic differentiation. These observations may explain the decreased mineralization previously observed in these types of cells.

SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury

“…Indeed, SPARC might act directly to influence cell fate in this example; conversely, the absence of SPARC might affect ECM assembly and/or localization of growth factors that in turn could influence differentiation. Rodriguez et al recently reported an analysis of the differentiative capacity of mesenchymal stem cells isolated from postmenopausal women with and without osteoporosis (20). Cells from osteoporotic patients produced less TGF-β and collagen I and exhibited an increased incidence of adipogenic differentiation in culture.…”

Intracellular VEGF regulates the balance between osteoblast and adipocyte differentiation

“…During aging, the balance between bone formation and resorption shifts in favor of resorption, resulting in reduced bone mass and altered bone architecture. In vitro, bone marrow mesenchymal stem cells from patients with osteoporosis are more likely to differentiate into adipocytes than osteoblasts compared with cells isolated from patients with normal bone mass (1), and osteoporotic bones have increased accumulation of adipocytes in the trabecular bone marrow space (2)(3)(4)(5). These studies and data from mouse models of osteoporosis have prompted questions about whether increased bone marrow fat is a consequence or the cause of decreased bone mass in osteoporosis (6).…”

Human Embryonic Stem Cell-Derived Mesenchymal Stem Cell Seeding on Calcium Phosphate Cement-Chitosan-RGD Scaffold for Bone Repair

“…First, the self-renewal and proliferative ability of hBMSCs decreases due to aging [17][18][19] and diseases, such as osteoporosis and arthritis. 20,21 Second, the heterogeneity of adult stem cells from bone marrow indicates that only a very small proportion of cells can be considered stem cells and can differentiate into the osteogenic lineage. 22 In this regard, hESCs hold great promise.…”