Chondrocytes Provide Morphogenic Signals That Selectively Induce Osteogenic Differentiation of Mesenchymal Stem Cells

Gerstenfeld, Louis C.; Cruceta, Johanna; Shea, Colleen M.; Sampath, Kuber T.; Barnes, George L.; Einhorn, Thomas A.

doi:10.1359/jbmr.2002.17.2.221

Cited by 113 publications

(101 citation statements)

References 47 publications

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“…Chondrocytes with Fgfr3 Deficiency Promote OsteogenesisDuring endochondral bone formation, cartilage formation precedes bone formation, and chondrocytes can provide inductive signals for osteogenesis (6,37). As bone formation was increased in mice with chondrocyte-specific deletion of Fgfr3, we suspected that the Fgfr3-deficient chondrocytes may affect osteogenesis in these FGFR3 mutant mice.…”

Section: Ablation Of Fgfr3 In Chondrocytes Results In Abnormal Growthmentioning

confidence: 99%

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Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Wen

Tang

et al. 2016

Journal of Biological Chemistry

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Edited by Xiao-Fan WangChondrogenesis can regulate bone formation. Fibroblast growth factor receptor 3, highly expressed in chondrocytes, is a negative regulator of bone growth. To investigate whether chondrocyte FGFR3 regulates osteogenesis, thereby contributing to postnatal bone formation and bone remodeling, mice with conditional knock-out of Fgfr3 in chondrocytes (mutant (MUT)) were generated. MUT mice displayed overgrowth of bone with lengthened growth plates. Bone mass of MUT mice was significantly increased at both 1 month and 4 months of age. Histological analysis showed that osteoblast number and bone formation were remarkably enhanced after deletion of Fgfr3 in chondrocytes. Chondrocyte-osteoblast co-culture assay further revealed that Fgfr3 deficiency in chondrocytes promoted differentiation and mineralization of osteoblasts by up-regulating the expressions of Ihh, Bmp2, Bmp4, Bmp7, Wnt4, and Tgf-␤1, as well as down-regulating Nog expression. In addition, osteoclastogenesis was also impaired in MUT mice with decreased number of osteoclasts lining trabecular bone, which may be related to the reduced ratio of Rankl to Opg in Fgfr3-deficient chondrocytes. This study reveals that chondrocyte FGFR3 is involved in the regulation of bone formation and bone remodeling by a paracrine mechanism.

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Section: Ablation Of Fgfr3 In Chondrocytes Results In Abnormal Growthmentioning

confidence: 99%

“…During endochondral bone formation, chondrocytes can provide inductive signals for osteogenesis (6,37). Because of the important effect of FGFR3 on chondrocyte differentiation (52), we wondered whether chondrocyte FGFR3 has an indirect influence on osteogenesis.…”

Section: Discussionmentioning

confidence: 99%

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Wen

Tang

et al. 2016

Journal of Biological Chemistry

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“…Because the activation of specific adhesion molecules and the induction of growth factors from progenitor or mature cells have been shown to promote differentiation of MSCs (7,25,26,40), a large number of genes that are involved in skeletogenesis were examined, in a temporal manner, using an array method. Integrins mediating cellular communication (41,42), or in this case, chondrocytic interactions, were moderately upregulated in MSCs under our coculture system.…”

Section: Discussionmentioning

confidence: 99%

“…To avoid such complications stemming from the implantation of undifferentiated MSCs, in vitro preconditioned MSCs may be used, since they appear to exert greater chondrogenic potential in promoting cartilage regeneration, and therefore may be considered a better candidate for OA treatment (21). A therapeutic strategy using MSCs could be an approach that guides the MSCs toward chondrogenesis by exposure to selected types of target cells (22)(23)(24)(25)(26).…”

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confidence: 99%

In vitro stage‐specific chondrogenesis of mesenchymal stem cells committed to chondrocytes

Chen

Lai

et al. 2009

Arthritis & Rheumatism

110

118

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Objective. Osteoarthritis is characterized by an imbalance in cartilage homeostasis, which could potentially be corrected by mesenchymal stem cell (MSC)-based therapies. However, in vivo implantation of undifferentiated MSCs has led to unexpected results. This study was undertaken to establish a model for preconditioning of MSCs toward chondrogenesis as a more effective clinical tool for cartilage regeneration.Methods. A coculture preconditioning system was used to improve the chondrogenic potential of human MSCs and to study the detailed stages of chondrogenesis of MSCs, using a human MSC line, Kp-hMSC, in commitment cocultures with a human chondrocyte line, hPi (labeled with green fluorescent protein [GFP]). In addition, committed MSCs were seeded into a collagen scaffold and analyzed for their neocartilage-forming ability.Results. Coculture of hPi-GFP chondrocytes with Kp-hMSCs induced chondrogenesis, as indicated by the increased expression of chondrogenic genes and accumulation of chondrogenic matrix, but with no effect on osteogenic markers. The chondrogenic process of committed MSCs was initiated with highly activated chondrogenic adhesion molecules and stimulated cartilage developmental growth factors, including members of the transforming growth factor ␤ superfamily and their downstream regulators, the Smads, as well as endothelial growth factor, fibroblast growth factor, insulin-like growth factor, and vascular endothelial growth factor. Furthermore, committed Kp-hMSCs acquired neocartilageforming potential within the collagen scaffold. Osteoarthritis (OA), one of the most common musculoskeletal diseases, has been ascribed to an imbalance in cartilage homeostasis in the aging process (1,2). Hyaline cartilage has little capacity for self-repair. As a result, continuous mechanical stress can lead to the degradation of articular cartilage, culminating in a vicious cycle of destructive processes (3). Many therapeutic interventions directed at the restoration of the reparative capacity of chondrocytes have been explored (3-5). One of the emerging approaches is cell-based therapy, in which expanded chondrocytes are used for cartilage repair. However, the outcome of this approach has been disappointing, due to the difficulties in maintaining chondrocytic phenotypes and the decrease in proliferative capacity of autologous chondrocytes with increasing age (1,6,7). Conclusion. These findings help define the molecular markers of chondrogenesis and more accuratelyCell therapy based on autologous mesenchymal stem cells (MSCs), which have a vast proliferative ca-

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“…However, it remains unclear as to whether and how osteoblasts affect the self-renewal and differentiation of another major stem cell population in bone marrow MSCs. There is little in vivo data available on this, and in vitro studies using conditioned medium or co-culture models have produced inconsistent results [13][14][15][16][17]. In experiments using conditioned medium, the real-time dynamic cell-cell interactions are missing and osteogenic inducers such as dexamethasone were used.…”

Section: Introductionmentioning

confidence: 99%

Osteogenic differentiation is synergistically influenced by osteoinductive treatment and direct cell–cell contact between murine osteoblasts and mesenchymal stem cells

Tsai

Lin

Huang

et al. 2011

International Orthopaedics (SICOT)

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Purpose The present study was designed to address whether osteoblasts play a synergistic role in promoting mesenchymal stem cell (MSC) osteogenesis in a direct cellcell contact co-culture model. Methods Murine C3H10T1/2 and MC3T3-E1 cell lines were mixed and plated onto 12-well culture plates and co-cultured at various ratios of initial cell densities. To compare the possible improvement on osteogenic differentiation, co-culture cells were served with or without osteogenic supplements in culture medium. Results Weak osteogenesis was induced in MSCs co-cultured in an untreated medium with different ratios of osteoblasts. An osteoblast-dependent increase in osteogenic gene expression of Runx2, type I collagen, and osteocalcin was observed over time. Moreover, both alkaline phosphatase (ALP) activity and calcium deposition were distinctly enhanced at levels that were proportional to the quantity of osteoblasts in the culture. The increases in mRNA expression and ALP activity were greater in co-cultures treated with osteogenic supplements than in untreated cultures. However, the production of ALP activity followed by a distinct matrix mineralization was lower in osteogenic-treated cultures containing greater numbers of osteoblasts. This suggests that a higher density of osteoblasts may lead to weak osteogenesis of MSCs by direct cell-cell contact co-culture in an untreated environment. Furthermore, additional osteogenic supplements may act synergistically with osteoblasts to accelerate matrix mineralization by reducing the process of osteogenic differentiation in osteogenic treated co-cultures. Conclusions The present work may improve the understanding of MSC osteogenesis and may provide benefits for regenerative medicine.

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Chondrocytes Provide Morphogenic Signals That Selectively Induce Osteogenic Differentiation of Mesenchymal Stem Cells

Cited by 113 publications

References 47 publications

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

Chondrocyte FGFR3 Regulates Bone Mass by Inhibiting Osteogenesis

In vitro stage‐specific chondrogenesis of mesenchymal stem cells committed to chondrocytes

Osteogenic differentiation is synergistically influenced by osteoinductive treatment and direct cell–cell contact between murine osteoblasts and mesenchymal stem cells

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