Background/Purpose: Osteoporosis is characterized by bone loss, increased fracture risk and reduced regeneration ability. Age-related bone loss leading to osteoporosis correlates with increased bone marrow fat infiltration and is characterized by an inverse relationship between bone mass and bone marrow adiposity. Bone marrow adipose tissue releases immunmodulatory (e.g. adipokines) and matrix-degrading proteins (e.g. matrix metalloproteinases, MMP) which promote bone loss observed in osteoporosis and osteoarthritis. Bone marrow adipocytes share mesenchymal stem cell (MSC) as precursors with osteoblasts. Therefore, adipocyte-derived factors might influence differentiation of bone marrow-derived MSC and be involved in the shift of differentiation from osteoblasts to adipocytes observed in osteoporosis. The aim was to analyze the presence of adipokines in the bone marrow cavity and their effects on MSC differentiation.

Methods: Spongiosa from femoral heads containing bone marrow were collected (hip replacement of osteoarthritis patients or after osteoporotic femoral neck fracture). Primary spongiosa-derived mesenchymal stromal cells (hMSC) and commercially obtained ‘normal’ MSC were cultured in adipogenic and osteogenic media 3 weeks with/without adipokines. Adipogenic differentiation was confirmed using Oil Red O staining. Realtime PCR for adipokines, bone marker genes, TIMP, MMP as well as of bone samples was performed. Matrix produced was stained and quantified using Alizarin S. Proinflammatory factors were measured by ELISA.

Results: Visfatin and leptin level were increased in osteoporotic bone (n=14) vs. non-osteoporotic bone (n=13). Visfatin induced the secretion of proinflammatory factors during both, osteogenic and adipogenic differentiation but not leptin or resistin (IL-6, IL-8, MCP-1). While MMP2 was reduced by stimulation of all adipokines during osteogenesis (n=3), visfatin reduced MMP13 expression during osteogenic differentiation (e.g. day 21: -55-fold) as well as TIMP1, -2 and RunX2 (e.g. day 21: -2.86-fold) / -3.17-fold / -5.85-fold, respectively) while leptin and resistin did not affect these parameters. Visfatin significantly increased matrix production during osteogenic differentiation. During adipogenesis, visfatin but not leptin or resistin stimulation of hMSC significantly increased MMP13 (e.g. day 21: 72-fold).

Conclusion: Visfatin and leptin were increased and resistin reduced in osteoporotic bone. MMP production was specifically reduced by visfatin during adipogenesis. Therefore, visfatin might promote bone destruction during increased adipogenic differentiation in osteoporosis. Of note, the shift towards osteogenic differentiation may be beneficial as visfatin appears to reduce MMP production during osteogenesis. Leptin had no direct effects on MSC differentiation in vitro, but could indirectly modulate bone degradation by affecting inflammatory cells.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/differentiation-of-spongiosa-derived-mesenchymal-stromal-cells-from-osteoporosis-and-osteoarthritis-patients-are-influenced-by-adipokines/