Human osteoclast cathepsin K is processed intracellularly prior to attachment and bone resorption

Cathepsin K is a member of the papain superfamily of cysteine proteases and has been proposed to play a pivotal role in osteoclast-mediated bone resor ption, We have developed a sensitive cytochemical assay to localize and qua ntify osteoclast cathepsin K activity in sections of osteoclastoma and huma n bone. In tissue sections, osteoclasts that are distant from bone express high levels of cathepsin K messenger RNA (mRNA) and protein. However, the m ajority of the cathepsin K in these cells is in an inactive zymogen form, a s assessed using both the cytochemical assay and specific immunostaining. I n contrast, osteoclasts that are closer to bone contain high levels of immu noreactive mature cathepsin K that codistributes with enzyme activity in a polarized fashion toward the bone surface. Polarization of active enzyme wa s clearly evident in osteoclasts in the vicinity of bone. The osteoclasts a pposed to the bone surface mere almost exclusively expressing the mature fo rm of cathepsin K, These cells showed intense enzyme activity, which was po larized at the ruffled border. These results suggest that the in vivo activ ation of cathepsin K occurs intracellularly, before secretion into the reso rption lacunae and the onset of bone resorption, The processing of procathe psin K( to mature cathepsin K occurs as the osteoclast approaches bone, sug gesting that local factors may regulate this process.