# Title: BMP/TGFbeta crosstalk in cartilage maintenance and osteoarthritis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $332,904

## Abstract

PROJECT SUMMARY
In the canonical pathway, TGFβs bind to their type I and II receptors TGFβRII and ALK5, respectively, to
activate Smads 2 and 3. It has been shown that Smad3 is essential for articular cartilage maintenance, but the
function of Smad2 in vivo is unknown. It has been shown that TGFβRII is not required for chondrogenesis
during development, but the function of the type I receptor ALK5 is unknown. This is an important gap in
knowledge because ALK5 can activate TGFβ pathways independently of TGFβRII. Moreover, ALK5 can
interact with the type I BMP receptor ALK1, enabling TGFβs to activate BMP pathways. We found that loss of
ALK5 leads to lethal chondrodysplasia, in contrast to the mild viable phenotype in mice lacking TGFβRII,
demonstrating that ALK5 acts independently of TGFβRII in cartilage. Furthermore, we found that Smad2/3
mutants are viable, demonstrating that ALK5 does not act primarily as a transducer of canonical TGFβ
signaling in cartilage. Unexpectedly, loss of ALK5 led to a significant increase in BMP output. Biochemical
studies pointed to ALK1 as the source of elevated BMP signaling. This was confirmed by our finding that loss
of Alk1 rescues the severe chondrodysplasia in Alk5 mutants. Our studies therefore uncover a new mechanism
of action for ALK5 as a regulator of BMP output and a previously unknown pathological role for ALK1 in
cartilage. We will investigate ALK1 and ALK5 action in growth plate cartilage in Aim 1. We also ablated Alk5 in
adult articular cartilage (AC). Mutants develop early onset osteoarthritis (OA)-like pathologies. We will address
whether ALK5 acts as a transducer of canonical TGFβ pathways and/or as an inhibitor of BMP signaling
through ALK1 in AC in Aim 2. Finally, we performed crosslinking, reporter, proximity ligation, and other assays
to investigate the basis for the genetic interaction between ALK1 and ALK5. These studies indicate that (a)
loss of ALK5 triggers the de novo formation of ALK1/ActRIIB complexes, and (b) provide evidence for ligand-
independent BMP signaling through ALK1 in cartilage. Prior in vitro studies have shown that ALK1 is unique
among BMP receptors in its ability to activate ligand-independent signaling, but the underlying mechanisms
and physiological relevance have never been investigated. We address these unknowns in Aim 3. In summary,
these studies demonstrate that the primary role of ALK5 is not to transduce TGFβ signals, but rather is to
prevent ligand-independent BMP signaling through ALK1 in cartilage. Completion of these studies could lead
to a significant revision of our understanding of the role of ALK5 and its critical importance in regulating
TGFβ/BMP crosstalk in cartilage.

## Key facts

- **NIH application ID:** 9921298
- **Project number:** 5R01AR073793-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Karen M. Lyons
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $332,904
- **Award type:** 5
- **Project period:** 2018-07-19 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921298

## Citation

> US National Institutes of Health, RePORTER application 9921298, Title: BMP/TGFbeta crosstalk in cartilage maintenance and osteoarthritis (5R01AR073793-03). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9921298. Licensed CC0.

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