Notice Number: NOT-AG-19-037

Key Dates
Release Date: September 4, 2019
First Available Due Date: October 5, 2019
Expiration Date: January 8, 2022

NOT-AG-24-002 - Notice of Special Interest (NOSI): Mechanisms of Osteoarthritis.

PA-19-053 NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-19-056 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

Issued by
National Institute on Aging (NIA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Purpose

Research Objectives

This Notice invites applications on research employing genetically defined and/or modified mouse models, other animal models such as dogs and monkeys, or archived human joint tissues to explore the biological mechanisms underlying the initiation and progression of osteoarthritis. Osteoarthritis (OA) is a significant problem in the aging population and is a major contributor to the mobility limitations endemic in this population, making it an important element in NIA's research mission. Inflammatory processes are evident in both aging and advanced stages of OA and are likely to be major contributors to the chronic pain that is the most common symptom of the condition. The initiating factor(s) responsible for OA are controversial. For the purpose of this announcement, osteoarthritis is distinguished from other joint diseases, such as rheumatoid arthritis, in which inflammation arising from autoimmunity is the primary cause of tissue damage. The root causes of joint degeneration in osteoarthritis remain unclear.

While aging is a major risk factor for osteoarthritis, research efforts in the past have focused primarily on the more advanced stages of osteoarthritis. Relatively little is known about the initial changes triggering disease etiology and early progression. This Notice is intended to encourage and accelerate the characterization of new or underutilized models as well as the testing of hypotheses that will lead to an improved understanding of the origins and mechanisms (both mechanical and molecular) mediating osteoarthritic progression.

Background

Osteoarthritis is the most common form of arthritis and the major cause of limitations in mobility and physical disabilities in older people. Current treatments for osteoarthritis are largely palliative, and many cases eventually require joint replacement with prostheses. Joint replacement is costly, and the finite functional life of prostheses can make a second replacement necessary, compounding the cost and risk for associated morbidity. Owing to the limited intrinsic repair capacity of the tissue, it is essential to identify the molecular defects responsible for causing OA. Understanding the root causes of joint degeneration would improve risk assessment and diagnosis at earlier stages of disease progression. Coupled with the development of preventive or therapeutic interventions, this could substantially reduce healthcare costs and substantially improve the quality of life for the elderly. The development of risk assessments, preventive strategies, and early-stage interventions for OA will be advanced by the identification of the molecular and cellular mechanisms that underlie the initiation and progressive deterioration of joint structure and function.

Osteoarthritis is characterized by degeneration of the articular cartilage surfaces of a joint. Within the cartilage environment, this degeneration is reflected in the functional decline and apoptosis of chondrocytes and by elevated levels of proteases known to participate in the further breakdown of extracellular matrix. The development of OA is strongly correlated with age, and the factors influencing joint structure and function are complex. The mechanical history of a joint, including both normal patterns of use and traumatic injury, is likely to be a major factor as well. In addition, genetic factors may predispose some individuals to develop OA at earlier ages.

Recent observations suggest that it may be useful to consider the joint as an integrated organ of bone, tendon, cartilage, and adipose tissue (infrapatellar fat pad). Recent reports that indicate active cross talk between bone, fat, brain, and the immune system via soluble blood-borne mediators. These reports suggest that the physiology of the joint may yet be considerably more complex than previously believed and are in part responsible for the development of the concept of metabolic OA. During skeletal development, the hypertrophic chondrocytes of growth plates normally undergo apoptosis, and cartilage is degraded and replaced by bone. In the regions that will become the articular surfaces of joints, cartilage is retained over a supporting region of subchondral bone. One hypothesis suggests that osteoarthritis reflects the inappropriate recurrence of the hypertrophic pathway in articular chondrocytes. The formation of bony outgrowths, or osteophytes, in osteoarthritic joints is consistent with this idea. If this hypothesis holds true, it follows that osteoarthritis may arise in part from disruption of normal mechanisms that establish and maintain the boundary between articular cartilage and subchondral bone. Thus, at least some of the causes of osteoarthritis may lie within the complex network of mechanisms that regulate the development and growth of the skeleton early in life.

The development of powerful methods for the genetic manipulation of mice has led to the creation of modified strains in which the consequences of specific genetic characteristics can be assessed in the intact animal and across the lifespan. The CRISPER CAS9 system may improve these approaches. In some instances, specific gene inactivation or over-expression results in age-related joint degeneration, with histological similarities to osteoarthritis. Several inbred mouse strains have also been observed to naturally develop osteoarthritis-like joint degeneration with age. Because both genetic and environmental factors may be precisely defined in the laboratory, these mouse models hold the potential to reveal genetic factors and hence the molecular pathways that influence the degeneration of joints. OA also occurs in larger mammalian species that may provide significant insights into the progression of osteoarthritis. In dogs, for example, some breeds are prone to osteoarthritis while other breeds appear to be resistant, while rabbits and horses have been used extensively in injury models of osteoarthritis. In the context of aging, the Hartley guinea pig is susceptible to OA naturally and should be a useful model.

Scope

Suggested research topics may include, but are not limited to, the following:

• Development of new models for studying age-related changes in OA
• Molecular characterization of disease pathology phenotypes of animal models exhibiting joint degeneration
• Identification of downstream effectors in pathways mediating effects of gene inactivation or transgene expression in genetically modified mice exhibiting joint degeneration
• The role of the aging immune system in the initiation of OA
• Understanding the age-related changes in metabolism that facilitate the initiation and/or progression of OA
• Identification of molecular mechanisms by which physical activity may ameliorate OA symptoms
• Mapping of genetic loci linked to joint degeneration in inbred mouse strains
• Characterization of changes at the chondro-osseous junction that precede or accompany degradation of the articular surface
• Testing of models of joint degeneration by specific antagonizing biological functions using anti-sense, dominant-negative, miRNA, lncRNA, or RNAi approaches
• Understanding the age-related changes in chondrogenic stem cells and their potential influence on the etiology of OA

Application and Submission Information

This notice applies to due dates on or after October 5, 2019 and subsequent receipt dates through January 8, 2022.

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcements through the expiration date of this notice.

• PA-19-053 NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
• PA-19-056 NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the FOA used for submission must be followed, with the following additions:

• For funding consideration, applicants must include NOT-AG-19-037 (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will be not be considered for this initiative.

Inquiries

Please direct all inquiries to:

John P. Williams, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-496-6403
Email: [email protected]

Anthony Kirilusha, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS)
Telephone: 301-451-7648
Email: [email protected]