Project Summary
Osteoarthritis (OA) is the most common form of arthritis, affecting 1 in 8 adults in the United States. It is
characterized by pain, stiffness, and swelling in the hands, hips, or knees, significantly impacting daily
functioning and overall quality of life. Current treatment approaches primarily focus on pain management rather
than addressing the underlying cause of OA: the degradation of articular cartilage (AC). AC is a smooth and
protective layer of hyaline cartilage that covers the ends of bones in synovial joints that is actively maintained
by long-lived articular cartilage chondrocytes (ACC). However, ACCs have limited regenerative capacity and
fail to repair AC after damage. Ultimately, AC damage leads to improper joint loading and further pathological
remodeling of the synovial joint, including AC ossification.
AC ossification occurs through the inappropriate activation of endochondral ossification-like programs,
similar to the development of growth plate chondrocytes (GPC) during embryogenesis. Interestingly, both
ACCs and GPCs originate from chondrocyte progenitors (CPs) in the developing limb. As skeletal elements
mature, CPs can differentiate into hypertrophic chondrocytes, which eventually form bone. In contrast, at the
prospective synovial joint site, CPs undergo a process of "dedifferentiation," downregulating Sox9 and Col2a1
to form a structure called the interzone (IZ). Cells within and around the IZ later develop into ACCs and other
components of synovial joints.
To investigate the critical decision between GPC and IZ/ACC fate, we employed gene regulatory
network (GRN) analysis and identified the transcription factors PITX1, ATF4, and SOX4 as regulators of CP
cell fate before interzone development. Notably, PITX1 and ATF4 have each been shown to bind the Sox9
promoter, but PITX1 and ATF4 are associated with different lineage biases (ACC and GPC, respectively). The
mechanisms underlying the maintenance of CP multipotency and the reprogramming of CPs to commit to ACC
differentiation remain unclear.
In our proposed project, we will utilize murine Sox9 lineage tracing models to characterize changes in
cell identity during differentiation. The objectives of the study are to determine: 1) the extent to which candidate
CP transcription factors, such as PITX1 and ATF4 exhibit mutually antagonistic effects and promote the
expression of ACC and GPC genes and 2) the requirement of CP reprogramming during IZ development for
ACC fate. We foresee that the completion of this project will reveal novel properties of synovial joint
development for potential therapeutic targeting.