Preliminary working model of WNT and BMP signaling feedback loop and perturbation by osteoarthritis factors. (A) WNT and BMP signaling reciprocally regulates the transcription of other antagonists. Exposure of WNT agonists leads to activation of WNT signaling . This activation results in the downregulation of WNT antagonists (for example, FRZB and DKK1), leading to less inhibition of WNT signaling . Additionally, BMP antagonists (for example, GREM1) are downregulated, leading to less inhibition of BMP signaling . Stronger BMP signaling results in the upregulation of WNT antagonists , establishing a negative feedback mitigating WNT signaling . This feedback loop allows for tight control of both BMP and WNT signaling in articular cartilage contributing to homeostasis. (B) Established factors that influence cartilage homeostasis also perturb this feedback loop. IL-1β, lack of mechanical stimulation and tonicity all decrease the mRNA levels of WNT and BMP antagonists, possibly resulting in a reset of the feedback loop, and contributing to the loss of cartilage homeostasis. BMP, bone morphogenetic protein; DKK1, dickkopf 1 homolog (Xenopus laevis); FRZB, frizzled-related protein; GADPH, glyceraldehyde 3-phosphate dehydrogenase; GREM1, Gremlin 1; WNT, wingless-type MMTV integration site.