Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway

Rosa, Renata Giardini; Collavino, Kristina; Lakhani, A.; Delve, E.; Weber, Joanna F.; Rosenthal, Ann K.; Waldman, Stephen D.

doi:10.1016/j.joca.2014.07.009

Cited by 22 publications

(13 citation statements)

References 52 publications

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“…Recently, the involvement of the purinergic signaling pathway in isolated chondrocytes was confirmed by experiments showing that stimulation with clodronate resulted in a threefold increase in Ca 2 + signaling, which could be efficiently inhibited through pharmacological inhibition of purinergic receptors (Rosa et al, ).…”

Section: Discussionmentioning

confidence: 95%

Chondrogenic Differentiation of Human Mesenchymal Stem Cells Results in Substantial Changes of Ecto‐Nucleotides Metabolism

Roszek

Porowińska

Bajek

et al. 2015

J of Cellular Biochemistry

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Mesenchymal stem cells (MSCs) are population of adult stem cells and attractive candidates for cartilage repair due to their chondrogenic potential. Purinergic compounds (purinergic receptors and ecto-enzymes metabolizing nucleotides), together with nucleotides/nucleosides present in the extracellular environment, are known to play a key role in controlling the stem cells biological potential to proliferate and differentiate. Despite the available literature pointing to the importance of purinergic signaling in controlling the fate of MSCs, the research results linking nucleotides and ecto-nucleotidases with MSCs chondrogenic differentiation are indigent. Therefore, the aim of presented study was the characterization of the ecto-nucleotides hydrolysis profile and ecto-enzymes expression in human umbilical cord-derived MSCs and chondrogenically induced MSCs. We described substantial changes of ecto-nucleotides metabolism and ecto-enzymes expression profiles resulting from chondrogenic differentiation of human umbilical cord-derived MSCs. The increased rate of ADP hydrolysis, measured by ecto-nucleotidases activity, plays a pivotal role in the regulation of cartilage formation and resorption. Despite the increased level of NTPDase1 and NTPDase3 mRNA expression in chondrogenically induced MSCs, their activity toward ATP remains quite low. Supported by the literature data, we hypothesize that structure-function relationships in chondrogenic lineage dictate the direction of nucleotides metabolism. In early neocartilage tissue, the beneficial role of ATP in improving biomechanical properties of cartilage does not necessitate the high rate of enzymatic ATP degradation.

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Section: Discussionmentioning

confidence: 95%

Chondrogenic Differentiation of Human Mesenchymal Stem Cells Results in Substantial Changes of Ecto‐Nucleotides Metabolism

Roszek

Porowińska

Bajek

et al. 2015

J of Cellular Biochemistry

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“…Immunohistochemical localization of collagen I and II was performed as previously described [24,25]. Briefly, cell pellets were fixed in 4% paraformaldehyde in PBS at 4 o C overnight, dehydrated in graded ethanol solutions and embedded in paraffin at 65 o C. Sections were cut at 5μm thickness and mounted on Superfrost slides.…”

Section: Immunohistochemical Staining For Collagen I and Iimentioning

confidence: 99%

Direct and indirect co-culture of bone marrow stem cells and adipose-derived stem cells with chondrocytes in 3D scaffold-free culture

Chiu¹,

Bianco²,

Giardini-Rosa³

et al. 2016

J Regen Med Tissue Eng

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Background: The use of chondrocytes for cartilage tissue engineering is hampered by the limited number of chondrocytes that can be harvested and potential dedifferentiation during cell expansion. While stem cells is a promising approach to create a large population of differentiated cells, multiple growth factors are typically required for differentiation. Alternatively, co-culturing of stem cells with mature chondrocytes can induce differentiation. However, it is not clear which stem cell population and co-culturing method best supports chondrogenesis. While co-culture of stem cells with chondrocytes has been extensively shown to improve chondrogenesis in general, results from previous reports were convoluted by the use of 2D culture or scaffold materials, resulting in discrepancies with the comparison between direct and indirect cocultures. Methods: The purpose of this study was to investigate the extent of chondrogenic differentiation of direct and indirect co-culture of bone marrow stem cells (BMSCs) or adipose-derived stem cells (ASCs) with mature chondrocytes in 3D scaffold-free culture. For direct co-culture, cell pellets were created by centrifugation, consisting of chondrocytes alone or different proportions of stem cells to chondrocytes. For indirect co-culture, cell pellets of chondrocytes or stem cells were created individually and cultured with a separation by a trans-well membrane. Chondrogenic differentiation potential was assessed by quantification of DNA, GAG and collagen contents, as well as collagen I, collagen II and Safranin-O staining. Statistical significance was analyzed using one-way ANOVA with Tukey's post-hoc tests. Results: Direct co-culture of chondrocytes with BMSCs resulted in superior chondrogenesis compared to all other co-culture methods. Cultures with the ratio of 3:1 BMSCs to chondrocytes stained positive for chondrogenic markers and displayed a uniform deposition of cartilaginous extracellular matrix. In addition, the extent of matrix deposition in direct BMSC co-cultures were comparable to growth factor differentiated BMSCs. Conclusions: Thus, BMSCs appear to be superior to ASCs in their differentiation capacity during coculture and a direct co-culture with chondrocytes (3:1 ratio) may be a feasible strategy for cartilage tissue engineering.

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“…A variety of bisphosphonates have been prescribed to human patients for several diseases of bone turnover, and clodronate more recently has been investigated for osteoarthritis [1][2][3][4]. Mechanisms of improved function in osteoarthritis patients may be due to clodronate's antiresorptive effect on chondrocytes and subchondral bone, or off-target mechanisms leading to a reduction in inflammatory cytokines and macrophages, or other mechanisms for antinociceptive activity [3][4][5][6][7][8][9][10][11][12]. Although the mechanism has not been investigated in the horse, reduced lameness in horses following bisphosphonate use has been demonstrated [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Clodronate improves lameness in horses without changing bone turnover markers

Mitchell

Wright

Sampson

et al. 2018

Equine Veterinary Journal

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Clodronate exerts an anabolic effect on articular chondrocytes mediated through the purinergic receptor pathway

Abstract: These findings support the previous notion that certain bisphosphonates may be useful as adjunctive therapies to potentially ameliorate progression of cartilage degeneration and improve arthritis management.

Cited by 22 publications

References 52 publications

Chondrogenic Differentiation of Human Mesenchymal Stem Cells Results in Substantial Changes of Ecto‐Nucleotides Metabolism

Chondrogenic Differentiation of Human Mesenchymal Stem Cells Results in Substantial Changes of Ecto‐Nucleotides Metabolism

Direct and indirect co-culture of bone marrow stem cells and adipose-derived stem cells with chondrocytes in 3D scaffold-free culture

Clodronate improves lameness in horses without changing bone turnover markers

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