Rosiglitazone Inhibits Bone Regeneration and Causes Significant Accumulation of Fat at Sites of New Bone Formation

Liu, Lichu; Aronson, James; Huang, Shu; Lu, Yalin; Czernik, Piotr J.; Rahman, Sima; Kolli, Vipula; Suva, Larry J.; Lecka‐Czernik, Beata

doi:10.1007/s00223-012-9623-4

Cited by 37 publications

(21 citation statements)

References 40 publications

(60 reference statements)

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“…Similarly, Oil Red O staining was performed on the cells cultured toward adipocytes for 10 days. All staining was performed following the manufacturer’s recommendations as we have described [20]. …”

Section: Methodsmentioning

confidence: 99%

Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease

Ruan

Trotter

et al. 2013

Bone

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A major cause of morbidity in patients with multiple myeloma is the development and progression of bone disease. Myeloma bone disease is characterized by rampant osteolysis in the presence of absent or diminished bone formation. Heparanase, an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate chains, is upregulated in a variety of human cancers including multiple myeloma. We and others have shown that heparanase enhances osteoclastogenesis and bone loss. However, increased osteolysis is only one element of the spectrum of myeloma bone disease. In the present study, we hypothesized that heparanase would also affect mesenchymal cells in the bone microenvironment and investigated the effect of heparanase on the differentiation of osteoblast/stromal lineage cells. Using a combination of molecular, biochemical, cellular and in vivo approaches, we demonstrated that heparanase significantly inhibited osteoblast differentiation and mineralization, and reduced bone formation in vivo. In addition, heparanase also shifts the differentiation potential of osteoblast progenitors from osteoblastogenesis to adipogenesis. Mechanistically, this shift in cell fate is due, at least in part, to heparanase-enhanced production and secretion of the Wnt signaling pathway inhibitor DKK1 by both osteoblast progenitors and myeloma cells. Collectively, these data provide important new insights into the role of heparanase in all aspects of myeloma bone disease and strongly support the use of heparanase inhibitors in the treatment of multiple myeloma.

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Section: Methodsmentioning

confidence: 99%

Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease

Ruan

Trotter

et al. 2013

Bone

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“…Diabetes significantly affects fracture repair, and it may have negative effects on new bone formation in distraction osteogenesis. The treatment of type II diabetes with Rosiglitazone may have further negative effect on bone formation [16], while treatment with Metformin may have positive effects [17]. …”

Section: Influence Of Disease Medication and Substance Abusementioning

confidence: 99%

The biology of bone lengthening

Hvid

Horn

Huhnstock

et al. 2016

Journal of Children's Orthopaedics

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Distraction osteogenesis biologically resembles fracture healing with distinctive characteristics notably in the distraction phase of osteogenesis. In the latency phase of bone lengthening, like in the inflammatory phase of fracture repair, interleukines are released and act with growth factors released from platelets in the local haematoma, leading to attraction, proliferation and differentiation of mesenchymal stem cells into osteoblasts and other differentiated mesenchymal cells. These in turn produce matrix, collagen fibers and growth factors. A callus containing cells, collagen fibers, osteoid and cartilage matrix is formed. Provided stable fixation, distraction will trigger intramembranous bone formation. As distraction proceeds, the distraction gap develops five distinctive zones with unmineralized bone in the middle, remodelling bone peripherally, and mineralizing bone in between. During consolidation, the high concentration of anabolic growth factors in the regenerate diminishes with time as remodelling takes over to form mature cortical and cancellous bone. Systemic disease, congenital bone deficiencies, medications and substance abuse can influence the quality and quantity of regenerate bone, usually in a negative way. The regenerate bone can be manipulated when needed by using injection of mesenchymal stem cells and platelets, growth factors (BMP-2 and -7), and systemic medications (bisphosphonates and parathyroid hormone). Growth factors and systemic anabolic and antiresorptive drugs are prescribed on special indications, while distraction osteogenesis is not an authorized indication. To some extent, however, these compounds can be used off-label. Use in children presents special problems since growth factors and specific anabolic medications may involve a risk of inducing cancer.

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“…Downregulation of PKIγ may be particularly useful for the approximately 20% patients who are unresponsive to therapy with intermittent PTH . Downregulation of PKIγ may also be useful to enhance repair of bone defects by mesenchymal precursor cells by programming their fate toward the osteoblastic lineage . For example, our demonstration of relatively long‐term knockdown of Pkig may provide a feasible approach to downregulate PKIγ ex vivo in mesenchymal precursor cells prior to their implantation in bone defects.…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Inhibitor γ Reciprocally Regulates Osteoblast and Adipocyte Differentiation by Downregulating Leukemia Inhibitory Factor

et al. 2013

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The Protein Kinase Inhibitor (Pki) gene family inactivates nuclear PKA and terminates PKA-induced gene expression. We previously showed that Pkig is the primary family member expressed in osteoblasts and that Pkig knockdown increases the effects of parathyroid hormone and isoproterenol on PKA activation, gene expression, and inhibition of apoptosis. Here, we determined whether endogenous levels of Pkig regulate osteoblast differentiation. Pkig is the primary family member in MEFs, murine marrow-derived mesenchymal stem cells, and human mesenchymal stem cells. Pkig deletion increased forskolin-dependent nuclear PKA activation and gene expression and Pkig deletion or knockdown increased osteoblast differentiation. PKA signaling is known to stimulate adipogenesis; however, adipogenesis and osteogenesis are often reciprocally regulated. We found that the reciprocal regulation predominates over the direct effects of PKA since adipogenesis was decreased by Pkig deletion or knockdown. Pkig deletion or knockdown simultaneously increased osteogenesis and decreased adipogenesis in mixed osteogenic/adipogenic medium. Pkig deletion increased PKA-induced expression of Leukemia Inhibitory Factor (Lif) mRNA and LIF protein. LIF neutralizing antibodies inhibited the effects on osteogenesis and adipogenesis of either Pkig deletion in MEFs or PKIγ knockdown in both murine and human mesenchymal stem cells. Collectively, our results show that endogenous levels of Pkig reciprocally regulate osteoblast and adipocyte differentiation and that this reciprocal regulation is mediated in part by LIF.

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Rosiglitazone Inhibits Bone Regeneration and Causes Significant Accumulation of Fat at Sites of New Bone Formation

Cited by 37 publications

References 40 publications

Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease

Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease

The biology of bone lengthening

Protein Kinase Inhibitor γ Reciprocally Regulates Osteoblast and Adipocyte Differentiation by Downregulating Leukemia Inhibitory Factor

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