Resorption parallel to the bone surface fits the concept of a dynamic sealing zone allowing the OC

to resorb and move simultaneously [30]. It also fits Parfitt’s conclusion from histological observations that OCs travel across the cancellous bone surface and not just perpendicular to the bone surface as sometimes inferred [9]. Interestingly, the distinct resorption pattern consisting of trenches and pits corresponds to the two types of resorption events identified in vivo in human trabecular bone through SEM, i.e. so-called “longitudinally extended resorption” reflecting long lasting resorption and “reticulate patch resorption” reflecting short episodes of intermittent resorption interrupted by migration [10]. The model presented in Fig. 7 provides a mechanistic basis to explain how agents acting on the Ibrutinib manufacturer AZD6244 in vitro collagenolysis–demineralization balance may contribute to steering

the resorptive activity of the OC on the bone surface. The intrinsic efficiency of OCs to degrade collagen is smaller than their efficiency to demineralize it, as clearly shown through the collagen left-overs of control OC cultures on bone slices. Thus, hormones stimulating CatK and collagenolysis like glucocorticoids will make resorption more continuous [17] and [31] and conversely hormones inhibiting CatK and collagenolysis like estrogen [32], [33] and [34] render resorptive events shorter [16]. As speculated by others [35], it would be intriguing to investigate in a systematic way to what extent CatK gene expression can be regulated

independently of demineralization and OC activation. In this respect, it is of interest that the response of CatK expression to calcineurin inhibition is much weaker compared to that of agents involved in the demineralization process, like ClC7 and carbonic anhydrase II [36], and compared to TRACP, and β3-integrin [37]. Furthermore, the response of CatK to estrogens was shown to be higher than that of DC-STAMP, NFATc1 and c-fos [33]. Of note, D-malate dehydrogenase collagenolysis can also be regulated independently of demineralization by agents acting directly on CatK enzymatic activity. Examples are the local redox potential [38], local nitric oxide levels [39], and also the maturation stage of the collagen molecule. Here it is of interest that older collagen is degraded faster by CatK than young collagen [40], which fits the observation that older bone is degraded more extensively than young bone by cultured OCs [41]. One may speculate in the same way that mutant collagen from osteogenesis imperfecta is more efficiently degraded, which would then explain the high bone resorption level in this disease [42] and [43].