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Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab. (Jöns Hilborn/Biomaterials)
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
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2015 (English)In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 3, 1197-1207 p.Article in journal (Refereed) Published
Abstract [en]

Current treatments for osteoporosis involve the administration of high doses of bisphosphonates (BPs) over a number of years. However, the efficiency of the absorption of these drugs and specificity towards targeted osteoclastic cells is still suboptimal. In this study, we have exploited the natural affinity of high (H) and low (L) molecular-weight hyaluronic acid (HA) towards a cluster of differentiation 44 (CD44) receptors on osteoclasts to use it as a biodegradable targeting vehicle. We covalently bonded BP to functionalised HA (HA–BP) and found that HA–BP conjugates were highly specific to osteoclastic cells and reduced mature osteoclast numbers significantly more than free BP. To study the uptake of HA–BP, we fluorescently derivatised the polymer–drug with fluorescein B isothiocyanate (FITC) and found that L-HA–BP could seamlessly enter osteoclastic cells. Alternatively, we tested polyvinyl alcohol (PVA) as a synthetic polymer delivery vehicle using similar chemistry to link BP and found that osteoclast numbers did not reduce in the same way. These findings could pave the way for biodegradable polymers to be used as vehicles for targeted delivery of anti-osteoporotic drugs.

Place, publisher, year, edition, pages
United Kingdom, 2015. Vol. 3, 1197-1207 p.
Keyword [en]
Bisphosphonates, Osteoporosis, Hyaluronic acid, Osteoclasts, Osteoblasts, Bone
National Category
Materials Chemistry
Research subject
Chemistry with specialization in Materials Chemistry; Chemistry with specialization in Polymer Chemistry
URN: urn:nbn:se:uu:diva-258090DOI: 10.1039/C5BM00096CISI: 000357937400003PubMedID: 26222035OAI: oai:DiVA.org:uu-258090DiVA: diva2:841062
EU, European Research Council

Erratum in Biomaterials Science 2015:3, issue 10, doi: 10.1039/c5bm90034d

Available from: 2015-07-10 Created: 2015-07-10 Last updated: 2015-12-18Bibliographically approved
In thesis
1. Evaluation of Functionalized Biopolymers as a Step Toward Targeted Therapy of Osteoporosis
Open this publication in new window or tab >>Evaluation of Functionalized Biopolymers as a Step Toward Targeted Therapy of Osteoporosis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The work presented in this thesis focuses on the development of strategies and smart bioactive materials for the treatment of osteoporosis. High and low molecular weight soluble hyaluronic acid-bisphosphonate (HA-BP) derivatives were investigated for their ability to inhibit osteoclasts. Low molecular weight HA-BP (L-HA-BP) was most effective in inhibiting active resorption of both murine and human osteoclasts (without affecting osteoblasts) compared to free bisphosphonate (BP). Precursor monocytes were unaffected, suggesting the specificity of HA-BP towards osteoclasts. This new class of functionalized hyaluronic acid could lead to rapid development of tailor-made pro-drugs for targeted treatment of osteoporosis.

Polyphosphoesters (PEP) have been widely studied for their pro-osteoblast effects, primarily due to their involvement in cellular energy production pathway leading to the formation of inorganic phosphates that contribute to mineralized bone. Given that the effect of PEP on human osteoclasts is little studied, this work on poly(ethylene sodium phosphate) (PEP.Na) explores the potential to use PEP.Na as an inhibitor of osteoclast activity for the first time. PEP.Na exposure led to a dose-dependent toxicity of osteoclasts with reduction in their capacity to form resorption pits over 24h.

Currently, there is a dearth of in vitro cell-culture systems that can study osteoclast-related resorption and osteoblast-related mineralization in a single co-culture system, and to simultaneously quantify the effects of soluble factors on these processes. Described here, is the development of a novel and simple two-sided co-culture system that can overcome these limitations with reliable and quantifiable readouts. In comparison with traditional one-sided co-culture systems, the two-sided co-culture was able to generate similar readouts for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) markers. There is also the advantage of distinctly separate and quantifiable readouts for mineralization and resorption, which has been demonstrated using Pamidronate.

Finally, HA-BP was synthesized with pre-determined amounts of BP groups. The BP groups attached to HA allowed the tunable incorporation of BMP-2 in hydrogels. The charge-based affinity of BMP-2 and BP allowed stable incorporation of specific amounts of BMP-2, which could be tuned by the ratio of BP groups. 125I-labelled BMP-2 was loaded into hydrogels and their release was studied. Radioactive measurements revealed the tunable sequestration and controlled release of protein over time. This result was corroborated by ALP measurements of cells exposed to released BMP-2. ALP production was found to be almost 5-fold higher in HA-BP hydrogels loaded with BMP-2 which suggested that the sequestered BMP-2 is not only available to cells but also remains highly potent, even in entrapped form, The release of BMP-2 is dependent upon the rate of diffusion, swelling in hydrogels and degradation pattern of the gels and may assist in the long-term and rapid regeneration of osteoblasts in vitro.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2015. 78 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1267
Osteoporosis, Bone regeneration, Biomaterials, Hyaluronic acid, Bisphosphonates, Osteoclasts, Osteoblasts, Growth factors
National Category
Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry; Chemistry with specialization in Materials Chemistry
urn:nbn:se:uu:diva-259386 (URN)978-91-554-9287-8 (ISBN)
Public defence
2015-09-24, Häggsalen, Ångström Laboratory, Lägerhyddsvägen 1, Uppsala, 09:00 (English)
Available from: 2015-08-28 Created: 2015-08-01 Last updated: 2015-10-01

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Kootala, SujitOssipov, DmitriHilborn, Jöns
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