Mechanisms of bone fragility in autosomal dominant osteopetrosis type II: from human to mouse and back

Active Project Grant Awarded Last action

Award ID
R01AR078914
Recipient
Awarding agency
Obligated
$4,499,061

Award facts

Completion date 88% complete
Place of performance
Boston, MA 02115, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Coupling, or communication between the bone-resorbing osteoclasts and bone-forming osteoblasts during bone remodeling, is a key step in the bone remodeling cycle. While compelling evidence shows that bone loss and fragility with age and osteoporosis result from corrupted coupling, the precise mechanism of osteoclast- osteoblast communication remains unclear. Thus, although stimulating coupling is a theoretically attractive therapeutic target, current treatments for osteoporosis, a common disorder affecting 54 million of the elderly in the US alone, are limited to either inhibiting osteoclastic bone resorption or stimulating osteoblastic bone formation. Our long-term goal is to determine the mechanism of osteoclast-osteoblast communication critical for coupling of bone formation to resorption during physiological bone remodeling, using rare osteopetrotic diseases as a tool. Rare bone diseases provide important insights into typical bone physiology and knowledge gained from these diseases has already led to new therapies for osteoporosis. In this proposal, we utilize samples from patients with autosomal dominant osteopetrosis type II (ADOII), a rare inheritable osteopetrosis characterized by high bone mass and skeletal fragility and complement human studies with mouse models. ADOII results from heterozygous mutations in the CLCN7 gene, which encodes the CLC-7 CL-/H+ exchanger essential for osteoclastic bone-resorption. While the lack of osteoclastic resorption clearly contributes to bone phenotype, bone formation is also inappropriately high. In preliminary data investigating the bone structural unit (BSU) composition of ADOII bones, we found bone formation is primarily remodeling based, with excess bone formation called overflow remodeling. Osteoclasts are abundant and scalloped cement lines suggest an intermittent PIT-like resorption mode, which in combination with overflow remodeling results in a characteristic puzzle-like bone structure. We hypothesize that the anabolically active but poorly resorptive osteoclasts in ADOII overexpress anabolic coupling factors, inappropriately stimulating bone formation to overfill the resorbed cavities and leading to disorganized puzzle-like bone and fragility. We will test this hypothesis by combining in vivo and in vitro studies of ADOII patients and mouse models, multimodal and multiscale imaging, biomechanics and spatial/single-nuclei transcriptomics. Specifically, we will: 1) test if the high bone mass and fragility in human and mouse ADOII is osteoclast-mediated; and 2) investigate the mechanism of inappropriately high bone formation in ADOII by single nuclei transcriptomic analysis of physically adjacent osteoclasts and osteoblasts. The proposed studies take advantage of the unique resource of extant iliac crest bone biopsy specimens from 15 ADOII patients from a danish family carrying the CLCN7 (G215R) mutation and age and SEX matched controls, and two mouse models of ADOII, including the analogous CLCN7G213R/+ mutation. Through the lens of ADOII, these studies will provide unique insights into osteoclast-osteoblast communication.

Transactions

Action Obligated Date
Amendment $131,719
Amendment $251,684
Amendment $127,550
Amendment $283,386
Amendment $412,092
Amendment $0
Amendment $0
Amendment $0
Amendment $0
Amendment $0
Amendment $452,041
Amendment $452,041
Amendment $452,041
Amendment $452,041
Amendment $0
Amendment $0
Amendment $0
Amendment $0
Amendment $0
Amendment $0
Amendment $494,822
Amendment $494,822
Original award $494,822
Show all 23

Subawards

Subrecipient Amount Awarded
Syddansk Universitet (University Of Southern Denmark) Dr. Andersen and his postdoc will meet with Dr. Charles and her lab members online every second week and physically twice a year in US or Denmark, or at… $259,269
Purdue University Dr. Wallace has over 20 years of experience working in the fields of bone mechanics and mechanobiology. Dr. Wallace will be responsible for supervising all… $108,387
Syddansk Universitet (University Of Southern Denmark) Dr. Andersen and his postdoc will meet with Dr. Charles and her lab members online every second week and physically twice a year in US or Denmark, or at… $512,903
Trustees Of Indiana University Dr. Wallace has nearly 20 years of experience studying mechanical properties of musculoskeletal tissues including bone and tendon. Dr. Wallace will be… $73,917

Quick answers

Who received award R01AR078914?

R01AR078914 was awarded to Brigham & Womens Hospital Inc. by National Insititue of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) on September 1, 2022.

How much is award R01AR078914 worth?

$4,499,061 has been obligated on R01AR078914.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login