# The role of endogenous low molecular weight mineralization inhibitors in spine health

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $666,008

## Abstract

Abstract
In vertebrates, calcium and phosphate form a metastable solution, from which they precipitate at specific
nucleation sites to form hydroxyapatite. Under physiological conditions, mineralization is restricted to skeleton
and teeth, despite the abundant presence of nucleation sites in soft connective tissues. The pathological
deposition of hydroxyapatite outside the boundaries of the skeleton, is known as ectopic mineralization, a
condition that affects millions of people around the globe. Ectopic mineralization is linked to a wide variety of
clinical conditions such as trauma, aging, cancer, diabetes, and autoimmune diseases, all major causes of
significant morbidity and mortality. Related to the skeleton, an understudied research area is the pathological
mineralization of spinal joints, and especially the tissues of the intervertebral disc (IVD). This is remarkable
considering the high prevalence of chronic low back and neck pain and associated IVD degeneration and spinal
pathologies and their dramatic socio-economic consequences. The major risk factor associated with back pain
is the degenerative status of the IVD and ectopic mineralization significantly contributes to this pathology. Current
information indicates that tissues are protected against uncontrolled mineralization by two classes of
complementary systems, proteins and low molecular weight (LMW) compounds (< 1000 Da). The first group
includes proteins like fetuin-A, osteopontin and Matrix Gla Protein whereas the best-known example of the
second class is inorganic pyrophosphate (PPi). Noteworthy, the role that citrate and phosphocitrate (PC), two
other endogenous metabolites that inhibit mineralization, play in the prevention of ectopic mineralization has
received surprisingly little attention. Moreover, how the extracellular levels of these endogenous LMW
compounds are regulated is incompletely understood. One major goal of this proposal is understanding the
mechanisms by which extracellular PPi together with citrate and PC regulate the mineralization of spinal and
other soft tissues. These studies will build on our previous work in which we identified the membrane proteins
ABCC6 and ANK as crucial factors in extracellular PPi homeostasis. We propose to delineate how these proteins
collaborate to prevent ectopic mineralization of IVD and other tissues. In addition, we recently discovered that
ANK regulates extracellular levels of citrate. We now plan to determine if extracellular citrate, which tightly binds
calcium, protects the IVD against dystrophic mineralization. Finally, we propose to elucidate the mechanisms
underlying synthesis and cellular extrusion of PC, an understudied but very potent endogenous mineralization
inhibitor. We expect that the proposed studies will provide mechanistic insight into how extracellular homeostasis
of PPi, citrate and PC is maintained, and how these metabolites prevent dystrophic mineralization of the IVD.
Moreover, we will determine if the...

## Key facts

- **NIH application ID:** 10803723
- **Project number:** 1R01AR082460-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Makarand V Risbud
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $666,008
- **Award type:** 1
- **Project period:** 2024-02-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10803723

## Citation

> US National Institutes of Health, RePORTER application 10803723, The role of endogenous low molecular weight mineralization inhibitors in spine health (1R01AR082460-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10803723. Licensed CC0.

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