BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells

Bais, Manish V.; Wigner, Nathan A.; Young, Megan; Toholka, Ryan; Graves, Dana T.; Morgan, Elise F.; Gerstenfeld, Louis C.; Einhorn, Thomas A.

doi:10.1016/j.bone.2009.04.239

Cited by 89 publications

(85 citation statements)

References 53 publications

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“…Cells were co-transfected using Fugene 6 reagent (150 l) (Roche), and 3 plasmids: lentivirus plasmid, pcMV-VSV-G and pCMVdR8.2 dvpr at the ratio of 8:1:8. Non-Target lentivirus plasmid served as a negative control (24). The supernatant fluid was collected at 24-h intervals for three consecutive days and was replaced with fresh differentiation media (35 ml).…”

Section: Methodsmentioning

confidence: 99%

Lysyl Oxidase-like-2 (LOXL2) Is a Major Isoform in Chondrocytes and Is Critically Required for Differentiation

Iftikhar¹,

Hurtado²,

Bais

et al. 2011

Journal of Biological Chemistry

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The lysyl oxidase family is made up of five members: lysyl oxidase (LOX) and lysyl oxidase-like 1-4 (LOXL1-LOXL4). All members share conserved C-terminal catalytic domains that provide for lysyl oxidase or lysyl oxidase-like enzyme activity; and more divergent propeptide regions. LOX family enzyme activities catalyze the final enzymatic conversion required for the formation of normal biosynthetic collagen and elastin cross-links. The importance of lysyl oxidase enzyme activity to normal bone development has long been appreciated, but regulation and roles for specific LOX isoforms in bone formation in vivo is largely unexplored. Fracture healing recapitulates aspects of endochondral bone development. The present study first investigated the expression of all LOX isoforms in fracture healing. A remarkable coincidence of LOXL2 expression with the chondrogenic phase of fracture healing was found, prompting more detailed analyses of LOXL2 expression in normal growth plates, and LOXL2 expression and function in developing ATDC5 chondrogenic cells. Data show that LOXL2 is expressed by pre-hypertrophic and hypertrophic chondrocytes in vivo, and that LOXL2 expression is regulated in vitro as a function of chondrocyte differentiation. Moreover, LOXL2 knockdown studies in vitro show that LOXL2 expression is required for ATDC5 chondrocyte cell line differentiation through regulation of SNAIL and SOX9, important transcription factors that control chondrocyte differentiation. Taken together, data provide evidence that LOXL2, like LOX, is a multifunctional protein. LOXL2 promotes chondrocyte differentiation by mechanisms that are likely to include roles as both a regulator and an effector of chondrocyte differentiation.The lysyl oxidase family is made up of five members: lysyl oxidase (LOX) 3 and lysyl oxidase-like 1-4 (LOXL1-LOXL4)(1). All five members share a conserved C-terminal catalytic domain that provides for lysyl oxidase or lysyl oxidase-like enzyme activity, and more divergent propeptide regions. LOX family enzyme activities catalyze the final enzymatic conversion required for the subsequent formation of normal lysinederived biosynthetic cross-links found in collagens and elastin (2). The importance of lysyl oxidase enzyme activity to normal bone development has long been known, and is based in part on studies in which enzyme activities are inhibited by lathyrogens in vivo (3), including ␤-aminopropionitrile, a potent inhibitor of LOX and LOX isoform activity (4). The LOX family can be subdivided into two subgroups. Although all members have similarities in the catalytic C-terminal region, LOX and LOXL1 are more closely related to each other than they are to LOXL2-LOXL4. Moreover, the pro-peptide regions of LOX and LOXL1 have very little similarity to each other and no similarity to LOXL2-LOXL4. The pro-regions of LOXL2-LOXL4 each contain four scavenger receptor cysteine-rich (SRCR) domains whose functions are likely to depend on interactions with other proteins (1). The pro-regions of all LOX family members may have...

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Section: Methodsmentioning

confidence: 99%

Lysyl Oxidase-like-2 (LOXL2) Is a Major Isoform in Chondrocytes and Is Critically Required for Differentiation

Iftikhar¹,

Hurtado²,

Bais

et al. 2011

Journal of Biological Chemistry

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“…Compared with the other BMP members, BMP-2 is a dominant factor in postnatal skeletal homeostasis (15). It has been demonstrated that osteoprogenitor cells from BMP-2-deficient mice exhibit impaired differentiation into fully functional osteoblasts (16,17). Limb-specific BMP-2 knockout mice have spontaneous fractures that fail to resolve with time, and other osteogenic stimulatory molecules cannot compensate for the lack of BMP-2 (18).…”

Section: Introductionmentioning

confidence: 99%

Coleusin Factor, a Novel Anticancer Diterpenoid, Inhibits Osteosarcoma Growth by Inducing Bone Morphogenetic Protein-2–Dependent Differentiation

Geng

Sun

et al. 2014

Molecular Cancer Therapeutics

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Coleusin factor is a diterpenoid compound isolated from the root of a tropical plant, Coleus forskohlii. Although Coleusin factor has been reported to suppress proliferation of and induce apoptosis in several types of cancer cells, the effects of Coleusin factor on osteosarcoma and the underlying mechanism are still not fully understood. In this study, we show that Coleusin factor treatment potently inhibits the growth of osteosarcoma cells associated with G 1 cell-cycle arrest. Interestingly, apoptosis and cell death are not induced. Instead, Coleusin factor causes osteosarcoma cells to exhibit typical properties of differentiated osteoblasts, including a morphologic alteration resembling osteoblasts, the expression of osteoblast differentiation markers, elevated alkaline phosphatase activity, and increased cellular mineralization. Coleusin factor treatment significantly increases the expression of bone morphogenetic protein-2 (BMP-2), a crucial osteogenic regulator, and runt-related transcription factor 2 (RUNX2), one of the key transcription factors of the BMP pathway. When BMP-2 signaling is blocked, Coleusin factor fails to inhibit cell proliferation and to induce osteoblast differentiation. Thus, upregulation of BMP-2 autocrine is critical for Coleusin factor to induce osteoblast differentiation and exert its anticancer effects on osteosarcoma. Importantly, administration of Coleusin factor inhibits the growth of osteosarcoma xenografted in nude mice without systemic or immunologic toxicity. Osteosarcoma is a highly aggressive cancer marked by the loss of normal differentiation. Coleusin factor represents a new type of BMP-2 inducer that restores differentiation in osteosarcoma cells. It may provide a promising therapeutic strategy against osteosarcoma with minimal side effects. Mol Cancer Ther; 13(6);

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“…Within BMPs, BMP-2 is an osteoinductive morphogen abundant in the bone extracellular matrix with proven activity on MSCs and defined roles in bone formation processes [24,25]. BMP-2 is extensively expressed in the growth plate, and its inhibition prevents osteogenic differentiation [26,27]. Likewise, the loss of BMP-2 in limb bud mesenchymal tissues leads to the inability to repair postnatal fractures [28], and the co-inactivation of both BMP-2 and BMP-4 results in severe osteogenesis impairment [29].…”

Section: Introductionmentioning

confidence: 99%

Bone Environment is Essential for Osteosarcoma Development from Transformed Mesenchymal Stem Cells

et al. 2014

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The cellular microenvironment plays a relevant role in cancer development. We have reported that mesenchymal stromal/stem cells (MSCs) deficient for p53 alone or together with RB (p53) originate leiomyosarcoma after subcutaneous (s.c.) inoculation. Here, we show that intrabone or periosteal inoculation of p53 2/2 or p53 2/2 RB 2/2 bone marrow-or adipose tissue-derived MSCs originated metastatic osteoblastic osteosarcoma (OS). To assess the contribution of bone environment factors to OS development, we analyzed the effect of the osteoinductive factor bone morphogenetic protein-2 (BMP-2) and calcified substrates on p53MSCs. We show that BMP-2 upregulates the expression of osteogenic markers in a WNT signaling-dependent manner. In addition, the s.c. coinfusion of p53 MSCs were inoculated embedded in a calcified ceramic scaffold composed of hydroxyapatite and tricalciumphosphate (HA/TCP), tumoral bone formation was observed in the surroundings of the HA/TCP scaffold. Moreover, the addition of BMP-2 to the ceramic/MSC implants further increased the tumoral osteoid matrix. Together, these data indicate that bone microenvironment signals are essential to drive OS development.

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BMP2 is essential for post natal osteogenesis but not for recruitment of osteogenic stem cells

Cited by 89 publications

References 53 publications

Lysyl Oxidase-like-2 (LOXL2) Is a Major Isoform in Chondrocytes and Is Critically Required for Differentiation

Lysyl Oxidase-like-2 (LOXL2) Is a Major Isoform in Chondrocytes and Is Critically Required for Differentiation

Coleusin Factor, a Novel Anticancer Diterpenoid, Inhibits Osteosarcoma Growth by Inducing Bone Morphogenetic Protein-2–Dependent Differentiation

Bone Environment is Essential for Osteosarcoma Development from Transformed Mesenchymal Stem Cells

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