ENPP1 regulation of mammalian bone mass

Inactivating
including
Ligament
early-onset
mutations in human ENPP1 results in aberrant soft tissue and skeletal mineralization disorders,
Autosomal Recessive Hypophosphatemic Rickets (ARHR2) Ossification of the Posterior Longitudinal
(OPLL), and Generalized Arterial Calcification of Infancy (GACI) in homozygous deficiency, and
osteoporosis (EOOP) in
,
ENPP1 haploinsufficiency. ENPP1 deficienct patients therefore exhibit
paradoxical mineralization, with concurrent low bone mass and progressive calcifications in kidneys, tendons,
and vasculature. Paradoxical mineralization is also present in the general medical population in aging patients,
and in patients with chronic kidney disease mineral and bone disorder (CKD-MBD). Fracture risk and high
mortality in CKD-MBD patients has not changed in the last 20 years despite significant progress in other
skeletal disorders, illustrating continued serious limitations in the understanding and treatment of CKD-MBD.
The study of ENPP1 deficiency and its inherent paradoxical mineralization, will serve to identify and validate
signaling pathways by which ENPP1 regulates bone mass; we strongly believe that this approach will inform
longstanding issues hampering our understanding of paradoxical mineralization, enabling better therapeutic
agents for these patients.
ENPP1 is the only human enzyme which generates PPi, a strong inhibitor of accrual of bone mineral in the
extant bone matrix. One would anticipate, therefore, that disorders inducing low PPi would result in increased
bone mass and volume, and not the low bone mass observed in humans and mice. Therefore, the mechanism
by which ENPP1 induces low bone mass is not apparent based on an understand of the enzyme's catalytic
activity alone. In response to this paradox, we hypothesize the presence of catalytically independent ENPP1
signaling pathways regulating mammalian bone mass. This proposal seeks to (a) establish the pathways
involved, (b) define the catalytically dependent and independent genetic and protein signal transduction
pathways by which ENPP1 regulates bone mass, and (c) quantitate their effect on bone fragility,
microarchitecture, and growth, as well as on biomarkers associated with bone mineralization. To accomplish
these Aims, we will use novel animal models which uncouple ENPP1 protein signaling from ENPP1 catalysis
and novel and proprietary biologics we have designed and engineered to activate ENPP1 catalytic and
catalytic-independent signaling in vivo. The investigative team has a strong history of success as evidenced by
several recent publications supporting the overall hypothesis, the specific aims, and the bench to bedside
development of a novel biologics treating GACI and ARHR2 that have entered the clinic, thus validating the
scientific rigor, experimental approach, and scientific impact of this proposal.

Grant Number: 5R01AR080416-04
NIH Institute/Center: NIH
Principal Investigator: DEMETRIOS BRADDOCK