Increased cathepsin D release by Hyp mouse osteoblast cells.

Abstract

The X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, is caused by loss-of-function mutations of PHEX (phosphate-regulating gene with homology to endopeptidases on the X chromosome) leading to rachitic bone disease and hypophosphatemia. Available evidence today indicates that the bone defect in XLH is caused not only by hypophosphatemia and altered vitamin D metabolism but also by factor(s) locally released by osteoblast cells (ObCs). The identity of these ObC-derived pathogenic factors remains unclear. In our present study, we report our finding of a prominent protein in the culture media derived from ObC of the hypophosphatemic (Hyp) mice, a murine homolog of human XLH, which was identified as the murine procathepsin D (Cat D). By metabolic labeling studies, we further confirmed that Hyp mouse ObCs released greater amount of Cat D into culture media. This increased Cat D release by Hyp mouse ObCs was unlikely to be due to nonspecific cell damage or heterogeneous cell population and was found to be associated with an increased Cat D expression at the protein level, possibly due to a reduced Cat D degradation. However, we were not able to detect a direct effect of PHEX protein on Cat D cleavage. In support of the involvement of Cat D in mediating the inhibitory effect of Hyp mouse ObC-conditioned media on ObC calcification, we found that exposure to Cat D inhibited ObC (45)Ca incorporation and that inhibition of Cat D abolished the inhibitory effect of Hyp mouse-conditioned media on ObC calcification. In conclusion, results from our present study showed that Hyp mouse ObCs release a greater amount of Cat D, which may contribute to the inhibitory effect of Hyp mouse ObC-conditioned media on ObC mineralization.

• Authors: Naoko Matsumoto, Oak D Jo, Remi N J Shih, Elsa J Brochmann, Samuel S Murray, Victor Hong, Jane Yanagawa, Norimoto Yanagawa
• Journal: American journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 289 Issue 1 Pg. E123-32 (Jul 2005) ISSN: 0193-1849 [Print] United States
• PMID: 15958652 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Proteins
• Cathepsin D
• PHEX Phosphate Regulating Neutral Endopeptidase
• PHEX protein, human
• Phex protein, mouse
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Cathepsin D (metabolism)
• Cell Line
• Hypophosphatemia (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Osteoblasts (drug effects, metabolism)
• PHEX Phosphate Regulating Neutral Endopeptidase
• Proteins (pharmacology)