Taming psoriatic keratinocytes—PTHs' uses go up another notch

AbstractThe native parathyroid hormone (PTH) and several of its N‐terminal adenylyl cyclase‐activating fragments and their analogs have become the star stimulators of bone growth for treating osteoporosis, accelerating fracture healing, and strengthening the anchorage of prosthetic bone implants and one of them (Lilly's Forteo™—recombinant hPTH‐(1‐34) has recently arrived in the clinic. But something entirely different has been lurking in the background—the ability of the adenylyl cyclase stimulating hPTH‐(1‐34) to calm hyperproliferating keratinocytes and reduce psoriatic lesions. By contrast PTH‐(7‐34) which cannot stimulate adenylyl cyclase actually stimulates keratinocyte proliferation. Normal keratinocytes make PTHrP after they lift off the basal lamina and have stopped cycling. But they have an unconventional PTH/PTHrP receptorr which is not coupled to adenylyl cyclase. Psoriatic keratinocytes do not make PTHrP and have only a broken‐down, proliferation‐limiting terminal differentiation‐driving Notch–Notch ligand mechanism. Putting these and other facts together produces a possible picture of an exogenously applied adenylyl cyclase‐activating PTH pinch hitting for the missing