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The osteopetroses reflect alterations of a special cell type, the osteoclast, belonging to the myeloid lineage. We have known this since the 1970s, confirmed by a myriad of reports featuring details that guided subsequent molecular diagnosis and treatment. This review is a tribute to two pioneers in the field: Donald G. Walker PhD (1925-1979) and Sandy C. Marks Jr. PhD (1937-2002), who explored osteopetrosis pathophysiology and treatment. Using spontaneous mutant models of osteopetrosis in mice, rats, and rabbits, they demonstrated the cellular basis of osteopetrosis while also advancing understanding of the hematological origin of osteoclasts. This became the foundation for life-saving treatment by hematopoietic stem cell transplantation. Their prose was uncomplicated, experiments were straightforward, and conclusions were based on facts explaining why their teaching became influential worldwide. I never met Dr. Walker but spoke with Dr. Marks on several occasions. Both inspired my work and, now appreciating how they shaped the osteoclast/osteopetrosis scientist community, we must thank these eminent scientists for being mentors of all of us.

Background Chronic recurrent multifocal osteomyelitis (CRMO) is a rare childhood disease presenting with bone pain, fever and multifocal osteolytic bone lesions. CRMO is considered an autoinflammatory disease but its aetiology and pathogenesis are still unknown. Autoinflammatory diseases are usually characterized by abnormalities in the regulation of inflammasomes, macromolecular complexes involved in the processing and in the release of IL-1?. Aim To investigate the inflammasome response in CRMO patients. Methods In this study, 10 CRMO patients (mean age 10.7 ± 5.4 years) and 9 age-matched controls were enrolled. The basal mRNA expression of inflammatory cytokines such as IL-1?, IL-6 and TNF-? and of inflammasome components such as ASC, NLRP3 and CASP-1 were evaluated by quantitative real-time PCR in peripheral blood mononuclear cells (PBMCs). IL-1? levels released in conditioned media after LPS and ATP treatment of PBMCs were measured by ELISA. Results mRNA levels of IL-1? and IL-6 were significantly higher in PBMCs from CRMO patients than in healthy donors, with a ten-fold average increase in IL1? transcript (p= 0.0001) and a five-fold average increase of IL-6 transcript (p=0.001). mRNA levels of inflammasome components were comparable between the two groups. When PBMCs were stimulated in vitro with LPS alone, we observed higher levels of IL-1? in the conditioned media of PBMCs obtained from CRMO patients than in those obtained from controls (p=0.01). Controls cells released high IL1? levels only after stimulation with LPS and ATP with no difference with PBMCs from CRMO patients. Conclusion Our data suggest that an abnormal regulation of IL-1? axis characterize PBMCs of CRMO patients.

The degradation of tissue inhibitor of metalloproteinase (TIMP)-free matrix metalloproteinase (MMP)-2 to proteolytically inactive fragments by plasmin was inhibited in equimolar mixtures of purified TIMP-2 and TIMP-free MMP-2 and was not observed in purified MMP-2-TIMP-2 complexes. Divalent cation chelators EDTA and sodium Alendronate did not inhibit plasmin degradation of TIMP-free MMP-2 but reversed the ability of TIMP-2 to protect MMP-2 from degradation by plasmin. Our data confirm a role for plasmin in the clearance of TIMP-free MMP-2, identify a pivotal role for TIMP-2 in regulating MMP-2 longevity in plasmin-containing environments, and highlight a novel therapeutic use for chelators of divalent cations, including the bisphosphonate Alendronate, in the reversal of TIMP-2 protection of MMP-2 from degradation by plasmin. We propose that these observations are relevant to pathologies that are dependent upon plasmin and MMP-2 activity (e.g., tumor invasion and metastasis).

In this study the effects of changes in intracellular pH on cytosolic Ca2+ were examined in single isolated osteoclasts. Alkalinization, performed by incubation in HCO3 containing buffer, induced increases in [Ca2+]. Conversely acidification, obtained by incubation in Na-butyrate-containing buffer induced a rapid and sustained decrease of [Ca2+]. The decrease of [Ca2+], during acidification with Na-butyrate was inhibited by VO4, an inhibitor of the Ca2+-ATPase. All these pieces of information indicate that changes in pH1 can modulate osteoclast activity together with modifications of [Ca2+], probably acting as intracellular signals.