Notice of Special Interest (NOSI): Mechanisms of Osteoarthritis
Notice Number:

Key Dates

Release Date:

February 29, 2024

First Available Due Date:
June 05, 2024
Expiration Date:
May 08, 2027

Related Announcements

  • May 7, 2020 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed). See NOFO PA-20-195.
  • May 5, 2020 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed). See NOFO PA-20-185.
  • September 4, 2019 - Notice of Special Interest: High-Priority Research Topics for PA-19-053 and PA-19-056. See Notice NOT-AG-19-037.

Issued by

National Institute on Aging (NIA)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)


This Notice of Special Interest (NOSI) 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 (OA). Osteoarthritis is a significant problem in the aging population and is a major contributor to mobility limitations endemic in this population and, therefore, is an important element in the research mission of NIA and NIAMS. Inflammatory processes are evident in aging and advanced stages of osteoarthritis 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 purposes 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, but there are three widely accepted routes: aging, traumatic injury, and obesity.

While aging is an important risk factor for osteoarthritis, research efforts in the past have focused primarily on the more advanced stages of osteoarthritis. Relatively little is understood about the initial changes triggering disease etiology and early progression. This NOSI is intended to encourage novel approaches to accelerate development and characterization of emerging or under-explored models as well as testing hypotheses that will lead to an improved understanding of the origins and mechanisms (both mechanical and molecular) mediating osteoarthritic progression or testing various therapeutic interventions for osteoarthritis.


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, with many cases finally requiring joint replacement with prostheses. Joint replacement is very 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. Emerging concepts in the field have highlighted the need to understand the interactions of all the tissues comprising the joint as a functional unit or organ in order to gain greater insight into the pathophysiology. 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 health care costs and substantially improve the quality of life for older people. 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 osteoarthritis 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 osteoarthritis at earlier ages.

Considering the joint as an integrated organ of bone, tendon/muscle, cartilage, synovium, and adipose tissue (infrapatellar fat pad) makes increasing sense in light of extensive tissue crosstalk networks being identified. Recent reports that indicate active cross talk between bone, fat, brain, and the immune system via soluble blood-borne mediators, suggest that the physiology of the joint may yet be considerably more complex than previously believed, and is 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 that regulate the development and growth of the skeleton early in life.

The development of powerful methods for the genetic manipulation of mice, such as CRISPR/CAS9, has led to the creation of modified strains in which the consequences of specific alterations in genetic characteristics can be assessed in the intact animal and across the lifespan. 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. In addition, large animal models for human osteoarthritis involve using animals that have similar joint anatomy and biomechanics to humans, making them valuable for studying the disease and testing potential treatments in a context that may more closely resembles the human condition. In dogs, for example, some breeds are prone to osteoarthritis while other breeds appear to be resistant. In addition, 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. Depending on the particular research interest, the joint size, anatomy, and arthroscopic access commonly favors the horse and the small ruminants, such as sheep and goat, for articular cartilage repair studies. Furthermore, in vitro models for osteoarthritis involve studying aspects of the disease using archived human joint tissues, and cell or tissue cultures in a controlled laboratory environment. These models allow researchers to investigate specific cellular and molecular mechanisms underlying osteoarthritis development and progression. Tissue-chip models have demonstrated the ability to replicate a wide range of physiological and pathological changes in synovial joints and osteoarthritis. It serves as a robust model for investigating joint pathology and advancing the development of innovative therapeutic interventions. Congress recently passed the FDA Modernization Act 2.0, effectively abolishing the requirement for animal testing in the drug approval process. As a result, the utilization of tissue chips for disease modeling and efficacy testing holds growing promise.


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

  • Molecular characterization of disease pathology phenotypes in joint degeneration;
  • Understanding the age-related changes in chondrogenic stem cells and their potential influence on the etiology of osteoarthritis;
  • Characterization of changes at the chondro-osseous junction that precede or accompany degradation of the articular surface;
  • The role of the aging immune system in the initiation of OA;
  • Defining the relationship between inflammatory signals and biological responses in joints, subchondral bone, and synovial tissue;
  • Identifying signaling pathways triggered by joint inflammation and their roles in joint degeneration;
  • Understanding the age-related changes in metabolism that facilitate the initiation and/or progression of OA;
  • Understanding the role of pro-inflammatory molecules associated with joint degradation and/or progression of OA;
  • Investigating molecular signals that link mechanical loading with gene expression and the effects of that signaling on joint health;
  • Understanding the role of joint non-articular cartilage tissues (nerves, synovium, muscle, fat, tendon etc.) to OA disease initiation and progression;
  • Mapping of genetic loci linked to joint degeneration;
  • Identification of downstream effectors in pathways mediating effects of gene inactivation or transgene expression in joint degeneration;
  • Defining the role of cellular senescence and aging-associated epigenetic changes on OA onset and progression;
  • Determining contributions of gene-gene and gene-environment interactions to overall genetic influence on OA susceptibility;
  • Using genetically modified animals and genomic analysis tools to understand the genetic components (including noncoding variants) involved in joint degeneration and to develop approaches for treating and preventing disease;
  • Identification of molecular mechanisms by which physical activity may ameliorate OA symptoms;
  • Studying the relationship between regenerative medicine and rehabilitation; and
  • Developing regenerative rehabilitation approaches to optimize self-healing and functional tissue recovery when combined with regenerative protocols for patients with knee osteoarthritis. 

Application and Submission Information

This notice applies to due dates on or after June 5, 2024 and subsequent receipt dates through May 8, 2027

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

  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

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

  • For funding consideration, applicants must include “NOT-AG-24-002” (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 not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed notice of funding opportunity with the following additions/substitutions:

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

Xincheng Zheng, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Disease (NIAMS) 
Telephone: 301-451-7648