Pigment Epithelium Derived Factor (PEDF) Influences Matrix Mineralization: Implications for Osteogenesis Imperfecta and Beyond

Patients with type VI Osteogenesis Imperfecta (OI) have mutations in the serpfin1 gene that lead to an absence of pigment epithelium derived factor (PEDF) production, and experience bone defects and frequent fracturing. A series of in vitro experiments performed by Feng Li, M.D., Ph.D., instructor, Penn State Hershey Orthopaedics and Rehabilitation, under the guidance of Christopher Niyibizi, Ph.D., are among the first to demonstrate a direct link between PEDF and a broad array of gene expression changes associated with increased osteoblast differentiation and matrix mineralization (Figure 1). The findings, recently published in Stem Cells¹ and Journal of Cellular Physiology², help to explain why patients with this rare subtype of OI experience bone fractures despite normal type 1 collagen expression and formation. The implications of the findings, however, extend to other conditions marked by decreased mineralization, like osteoporosis.

Osteogenesis Imperfecta (OI)

FIGURE 1. PEDF increases mineral deposition by mineralizing osteoblasts and suppresses sclerostin production by osteocytes. A) Osteoblasts were cultured in osteogenic medium in presence or absence of exogenous PEDF for twenty-one days. Analysis of mineral deposition by Alizarin red S staining (AR-S) showed increased mineral deposition in cultures supplemented with PEDF. B) Sclerostin production by osteocytes in mineralizing cultures was detected beginning at two weeks, and cultures supplemented with exogenous PEDF reduced production of sclerostin by osteocytes.

For the experiments, exogenous PEDF was added to the osteogenic culture medium of adult human mesenchymal stem cells, PEDF enhanced the cells’ differentiation and increased mineralization in vitro¹. According to Niyibizi, “Among the more pronounced effects of exogenous PEDF were the 70 to 75 percent reductions in sclerostin and matrix extracellular phosphoglycoprotein expression (MEPE) by osteocytes².” Sclerostin is a strong inhibitor of bone formation and MEPE inhibits matrix mineralization; with addition of PEDF to the mineralizing medium, matrix mineralization significantly increased, compared to cultures without exogenous PEDF.

Likewise, exogenous PEDF in cultures of mineralizing human osteoblasts led to significantly increased expression of bone sialoprotein and collagen type 1, indicating accelerated osteoblast differentiation and maturation, compared to osteoblasts without PEDF added to the culture medium.

Niyibizi says, “We are now very interested in isolating and studying, in vitro and in vivo, the protein-derived fragments of the PEDF molecule that bind to osteoblasts or osteocyte PEDF-receptors to accelerate osteoblasts differentiation or inhibit sclerostin production. Because of multi-functionality of PEDF, different regions of the molecule perform different functions. Thus, the key to PEDF’s regulatory actions on genes that control bone cell differentiation, maturation, and matrix mineralization may be due to specific regions of PEDF.

The PEDF peptide and osteocyte receptor complex may be a potential therapeutic target not only in OI, but in other conditions where decreased bone formation and mineralization occurs, such as osteoporosis and end-stage renal disease. The experiments suggest that a PEDF-based treatment may have broad implications in bone pathologies.


Christopher Niyibizi, Ph.D.Christopher Niyibizi, Ph.D.
Associate Professor, Orthopaedics and Rehabilitation; Biochemistry and Molecular Biology; Anatomy
PHONE: 717-531-5649
E-MAIL: cniyibizi@psu.edu
GRADUATE STUDY: McGill University, Montreal, Canada
POST-DOCTORAL TRAINING: Harvard Medical School, Boston, Massachusetts, and University of Washington School of Medicine, Seattle, Washington


REFERENCES:

1. Li, F, Song N, Tombran-Tink J, Niyibizi C. 2013. Pigment epithelium derived factor enhances differentiation and mineral deposition of human mesenchymal stem cells. 31:2714-23.
2. Li, F, Song N, Tombran-Tink J, Niyibizi C. 2014. Pigment epithelium-derived factor suppresses expression of Sost/sclerostin by osteocytes: Implication for its role in bone matrix mineralization. J Cellular Physiol. Nov 3. doi: 10.1002/jcp.24859. [Epub ahead of print]

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