Human Trabecular Bone Cells Are Able to Express Both Osteoblastic and Adipocytic Phenotype: Implications for Osteopenic Disorders

Abstract

The decrease in bone volume associated with osteoporosis and age-related osteopenia is accompanied by increased marrow adipose tissue formation. Reversal of this process may provide a novel therapeutic approach for osteopenic disorders. We have shown that cells cultured from human trabecular bone are not only osteogenic, but are able also to undergo adipocyte differentiation under defined culture conditions. Osteoblast differentiation was induced by 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) and adipocyte differentiation by dexamethasone (dex) plus 3-isobutyl-1-methylxanthine (IBMX) treatment. Adipogenesis was characterized by lineage-specific enzyme and gene activities, ␣-glycerophosphate-3-dehydrogenase activity, fatty acid binding protein, aP2 and lipoprotein lipase expression. Osteoblastogenesis was assessed by osteoblast characteristic 1,25(OH) 2 D 3 induction of alkaline phosphatase activity and osteoblast-specific 1,25(OH) 2 D 3 -induced osteocalcin synthesis and release. We provide evidence for a common pluripotent mesenchymal stem cell that is able either to undergo adipogenesis or osteoblastogenesis, using clonal cell lines derived from human trabecular bone cell cultures. Adipogenesis can be induced also by long chain fatty acids and the thiazolidinedione troglitazone. Dex plus IBMX-induced adipogenesis can be inhibited by interleukin-1␤, tumor necrosis factor-␣, and transforming growth factor-␤. Interestingly, and in contrast to extramedullary adipocyte differentiation as shown by mouse 3T3L-1 and a human liposarcoma SW872 cell line, trabecular bone adipogenesis was unaffected by insulin. Also, the formation of fully differentiated adipocytes from trabecular bone cells after troglitazone treatment and long chain fatty acids was dependent on increased expression of the nuclear hormone receptor peroxisome proliferator-activated receptor ␥2 caused by dex plus IBMX. Specific inhibition of marrow adipogenesis and promotion of osteoblastogenesis of a common precursor cell may provide a novel therapeutic approach to the treatment of osteopenic disorders. (J Bone Miner Res 1998; 13:371-382)

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…In addition, the inhibitory role of PPARγ on maturation of various osteoblastic cell lines concomitant with adipocytic differention has been well established [137][138][139].…”

Effects of arachidonic acid and docosahexaenoic acid on differentiation and mineralization of MC3T3‐E1 osteoblast‐like cells

“…24,25,27 Figure 3. Photomicrograph of mineralized nodules after 14 days of exposure to polyunsaturated fatty acids.…”

“…23 These receptors are activated by free fatty acids and their oxidation products as well as by some prostaglandins derived from fatty acids that induce the differentiation of preadipocytes into adipocytic cells. [24][25][26][27] AA, which is a precursor for prostaglandins of the -2-family, has specifically been implicated in adipocyte differentiation. 23 With ageing there is a decrease in osteoprogenitor cells with an accompanying increase in adipocytes in bone marrow.…”

“…This is due to altered differentiation of the common precursor cell, the mesenchymal stem cell (MSC). 23,25,28 Results from our laboratory have shown that AA (n-6 PUFA) and DHA (n-3 PUFA), at physiological concentrations (2.5-20 mg ml À1 ), inhibit osteoblast cell proliferation in a dose-dependent manner. 29 Since there is a reciprocal relationship between reduced proliferation and subsequent induction of cell differentiation in vitro, 20,21,30 the effects of AA and DHA on osteogenesis was investigated.…”

Three-dimensional cultures of normal human osteoblasts: proliferation and differentiation potential in vitro and upon ectopic implantation in nude mice

“…3,23,28,33 Also, cell-cell interactions via gap junctions, 6,9 cell shape, and cytoskeletal organization, dependent on integrin-mediated interaction with specific components of the endogenous extracellular matrix (ECM), 27,31 have been shown to determine cell metabolism, gene expression and differentiation, and cellular response to stimuli. 17 Osteoblast survival and apoptosis 4,19 depend on endogenous growth factors, and often associated with the ECM.…”