Degradation of the Organic Phase of Bone by Osteoclasts: A Secondary Role for Lysosomal Acidification
Open Access
- 1 January 2006
- journal article
- Published by Oxford University Press (OUP) in Journal of Bone and Mineral Research
- Vol. 21 (1), 58-66
- https://doi.org/10.1359/jbmr.050905
Abstract
Osteoclasts degrade bone matrix by secretion of hydrochloric acid and proteases. We studied the processes involved in the degradation of the organic matrix of bone in detail and found that lysosomal acidification is involved in this process and that MMPs are capable of degrading the organic matrix in the absence of cathepsin K. Osteoclasts resorb bone by secretion of acid by the vacuolar H+-adenosine triphosphatase (V-ATPase) and the chloride channel ClC-7, followed by degradation of the matrix, mainly collagen type I, by cathepsin K and possibly by matrix metalloproteinases (MMPs). However, the switch from acidification to proteolysis and the exact roles of both the ion transporters and the proteinases still remain to be studied. We isolated CD14+ monocytes from human peripheral blood from either controls or patients with autosomal dominant osteopetrosis type II (ADOII) caused by defective ClC-7 function and cultured them in the presence of RANKL and macrophage-colony stimulating factor (M-CSF) to generate osteoclasts. We decalcified cortical bovine bone slices and studied the osteoclasts with respect to morphology, markers, and degradation of the decalcified matrix in the presence of various inhibitors of osteoclast acidification and proteolysis, using normal calcified bone as a reference. We found that ADOII osteoclasts not only have reduced resorption of the calcified matrix, but also 40% reduced degradation of the organic phase of bone. We found that both acidification inhibitors and cathepsin K inhibitors reduced degradation of the organic matrix by 40% in normal osteoclasts, but had no effect in the ADOII osteoclasts. Furthermore, we showed that inhibition of MMPs leads to a 70% reduction in the degradation of the organic bone matrix and that MMPs and cathepsin K have additive effects. Finally, we show that osteoclastic MMPs mediate release of the carboxyterminal telopeptide of type I collagen (ICTP) fragment in the absence of cathepsin K activity, and therefore, to some extent, are able to compensate for the loss of cathepsin K activity. These data clearly show that osteoclastic acidification of the lysosomes plays a hitherto nonrecognized role in degradation of the organic matrix. Furthermore, these data shed light on the complicated interplay between acidification dependent and independent proteolytic processes, mediated by cathepsin K and the MMPs, respectively.Keywords
This publication has 55 references indexed in Scilit:
- Acidification of the Osteoclastic Resorption Compartment Provides Insight into the Coupling of Bone Formation to Bone ResorptionThe American Journal of Pathology, 2005
- The relative contribution of cysteine proteinases and matrix metalloproteinases to the resorption process in osteoclasts derived from long bone and scapulaBone, 2004
- The Chloride Channel Inhibitor NS3736 Prevents Bone Resorption in Ovariectomized Rats Without Changing Bone FormationJournal of Bone and Mineral Research, 2004
- The Type I Collagen Fragments ICTP and CTX Reveal Distinct Enzymatic Pathways of Bone Collagen DegradationJournal of Bone and Mineral Research, 2003
- Effects of Bafilomycin A1: An inhibitor of vacuolar H (+)‐ATPases on endocytosis and apoptosis in RAW cells and RAW cell‐derived osteoclastsJournal of Cellular Biochemistry, 2003
- Immunolocalization of vacuolar‐type H+‐ATPase, cathepsin K, matrix metalloproteinase‐9, and receptor activator of NFkB ligand in odontoclasts during physiological root resorption of human deciduous teethThe Anatomical Record, 2001
- Cysteine Proteinases and Matrix Metalloproteinases Play Distinct Roles in the Subosteoclastic Resorption ZoneJournal of Bone and Mineral Research, 1998
- Localization of cathepsin K in human osteoclasts by in situ hybridization and immunohistochemistryBone, 1997
- Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosisBone, 1993
- Inhibition of osteoclast proton transport by bafilomycin A1 abolishes bone resorptionBiochemical and Biophysical Research Communications, 1990