# CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Novel cell-based therapies to increase functional outcomes and alleviate pain in preclinical models of osteoarthritis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Overall Research Strategy: The overall goal of the CaRa-AP Collaborative Program is to develop a treatment
for post-traumatic osteoarthritis (PTOA) that will relieve pain and improve function. We hypothesize that PTOA
is caused by maladaptive repair responses including activation of the pro-inflammatory pathways of innate
immunity that in turn result in pain, loss of function and structural decline. This Program addresses the hypothesis
through two highly-integrated aims: (1) innovative intra-articular treatments using small molecules, biologic
inhibitors and immunomodulatory cells to reduce pain and inflammation in the joint and (2) tissue engineering
using stem cell-based therapies for reconstruction of the damaged joint infrastructure. The investigators
collaborating in this program will coordinate testing of therapies in four animal models that mimic different
mechanisms of injury that initiate PTOA in patients. The experiments will take into consideration relevant factors
affecting joint physiology and treatment response. The effects of different therapeutic modalities will be evaluated
using group-standardized measurements of pain, function, inflammation and structure, so that results can be
compared across laboratories and the most promising therapeutic strategies prioritized for clinical trials.
We provide compelling evidence that sequential treatment of mesenchymal progenitors with BMP2 and non-
canonical Wnt5a, cultured in high density pellets, yield articular-like cells in vitro. These effects are reproduced
when small molecules Kartogenin (KGN), a chondrogenic small molecule targeting Runx1, and Foxy5, a Wnt5a
mimetic peptide, are sequentially used. Moreover, implantation of pellets, treated with BMP2 followed by Wnt5a,
into a rat chondral defect regenerate articular-like cartilage. Our preliminary data also demonstrate an influence
of physical exercise on cartilage preservation and joint function in a rat model of PTOA. Thus, we ask whether
the source of stem cells can differentially promote hyaline cartilage regeneration and if physical rehabilitation
can improve pellet integration and treatment outcome. Specifically, we aim to compare the efficacy of somatic
cells (human articular chondrocytes and bone marrow derived mesenchymal stem cells) to that of patient-
specific, and readily available, pluripotent stem cells. We hypothesize that cell plasticity will determine the
potential of adult versus pluripotent stem cells to treat cartilage degeneration, and that successful
restoration of cartilage integrity via cellular and physical therapy will lead to enhanced functional
outcomes and reduced nociception in vivo.
We will first establish the capacity of iPSC-derived MSCs to that of adipose-derived and human articular
cartilage MSCs with and without sequential treatment with KGN and Foxy5 to regenerate articular cartilage
following implantation of control or treated high-density pellets into a rat chondral defect model of PTOA.
Histolo...

## Key facts

- **NIH application ID:** 10013786
- **Project number:** 1I01BX004878-01A1
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Moulay Hicham DRISSI
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013786

## Citation

> US National Institutes of Health, RePORTER application 10013786, CMA: Cartilage Repair Strategies to Alleviate Arthritic Pain (CaRe AP): Novel cell-based therapies to increase functional outcomes and alleviate pain in preclinical models of osteoarthritis (1I01BX004878-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013786. Licensed CC0.

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