Date of Completion

3-15-2018

Embargo Period

3-15-2018

Keywords

osteoarthritis, fgf2, fgf23

Major Advisor

Dr. Marja Hurley

Associate Advisor

Dr. Caroline Dealy

Associate Advisor

Dr. Sun-Kyeong Lee

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Osteoarthritis (OA) the most common degenerative joint disease, characterized by articular cartilage degradation, has no cure and molecular mechanisms which cause the disease remain largely unknown. Although fibroblast growth factor 2 (FGF2) has been implicated in OA pathogenesis, previous findings showed contrasting roles and never examined if/how the varying isoforms (high molecular weight, HMW, or low molecular weight, LMW), in which the FGF2 gene encodes, contribute to the disease. Clearly, there is a need to further understand the involvement of FGF2 isoforms in OA pathophysiology, which is the purpose of this research study.

Using novel mouse models in which HMW or LMW FGF2 isoforms have been ablated (Fgf2HMWKO and Fgf2LMWKO mice) or overexpressed (HMWTg or LMWTg mice) we explored the role the isoforms play in OA. HMWTg mice phenocopy most traits in humans with X-linked hypophosphatemic rickets (XLH) and its murine homologue, the Hyp mouse, including increased FGF23 levels. Subjects with XLH and Hyp mice develop osteoarthropathy, and Hyp mice overexpress HMW FGF2 isoforms, which co-localized with FGF23 in HMWTg mice. There is crosstalk between FGF23 and Wnt/β-catenin signaling, both catabolic regulators in OA, and both upregulated in Hyp mice. Thus, we hypothesized that mice overexpressing HMW FGF2 isoforms will develop OA, due to increased FGF23 that is propating the canonical Wnt signaling cascade. Mice only expressing HMW FGF2 isoform (Fgf2LMWKO mice) will develop OA, unlike mice only expressing LMW FGF2 (Fgf2HMWKO mice).

We assessed for signs of OA in these FGF2 isoform transgenic and knockout mice and found that HMWTg and Fgf2LMWKO mice had loss of articular cartilage, increased OA markers abnormal subchondral bone structures, and increased FGF23/FGFR1 expression as indicated by radiography/microCT, histology, and qPCR analyses. HMWTg chondrocytes had increased expression of canonical Wnt signaling components, FGF23, and OA markers which were rescued after inhibition of Wnt as indicated by histology, qPCR, and Western blot analyses. OA was partially attenuated in HMWTg mice after neutralizing FGF23Ab treatment.

Thus, HMW FGF2 modulates FGF23/FGFR1/Wnt/β-catenin signaling-mediated OA in chondrocytes, offering new insight into FGF2 and OA pathogenesis and a potential pathway to target in the future treatment of the disease.

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