Ostm1 from Mouse to Human: Insights into Osteoclast Maturation

Abstract

The maintenance of bone mass is a dynamic process that requires a strict balance between bone formation and resorption. Bone formation is controlled by osteoblasts, while osteoclasts are responsible for resorption of the bone matrix. The opposite functions of these cell types have to be tightly regulated not only during normal bone development, but also during adult life, to maintain serum calcium homeostasis and sustain bone integrity to prevent bone fractures. Disruption of the control of bone synthesis or resorption can lead to an over accumulation of bone tissue in osteopetrosis or conversely to a net depletion of the bone mass in osteoporosis. Moreover, high levels of bone resorption with focal bone formation can cause Paget’s disease. Here, we summarize the steps toward isolation and characterization of the osteopetrosis associated trans-membrane protein 1 (Ostm1) gene and protein, essential for proper osteoclast maturation, and responsible when mutated for the most severe form of osteopetrosis in mice and humans.

The lysosomal chloride-proton exchanger CLC7 functions in melanosomes as a negative regulator of human pigmentation

“…1E), similar to the mouse hair phenotype. The unexpected difference in the direction of the pheomelanin changes in HEMs with downregulation of CLC7 compared to OSTM1 imply that OSTM1 might have cellular functions independent of CLC7, as previously suggested (16,17). The difference between the effect of CLC7 downregulation on mouse and human pigmentation, while surprising, could be attributed to different mechanisms governing hair and skin pigmentation, or to the absence of CLC7 expression during early developmental stages in mice (14,37).…”

“…The pigmentation phenotype of human melanocytes only partially recapitulates the pigmentation phenotype of the CLC7 -/and OSTM1 -/mice, both of which show reduced pheomelanin levels (15,17). In contrast, human melanocytes with CLC7 downregulation have increased pheomelanin, whereas OSTM1 downregulation leads to less pheomelanin ( Fig.…”

“…Among these, the chloride/proton (Cl -/H + ) exchanger Chloride Channel 7 (CLC7) and its obligate β-subunit Osteopetrosis-Associated Transmembrane Protein 1 (OSTM1) were highly enriched in epidermal melanocytes compared to keratinocytes (13). Interestingly, CLC7 −/− mice have grey fur in an agouti background (14,15), a coat color phenotype also shared by the OSTM1 −/− grey-lethal mice (16,17), demonstrating that both CLC7 and OSTM1 regulate mouse fur pigmentation, but via unknown mechanisms.…”

Determinantes de la densidad mineral ósea y el papel del ejercicio físico con cargas en personas mayores

“…El resultado de este recambio de tejido es la mantención de los huesos sanos y mecánicamente competentes (13) . Una alteración del equilibrio entre la actividad de los osteoblastos y de los osteoclastos conduce a una pérdida excesiva de masa ósea (osteoporosis) o a una pérdida parcial de esta (osteopenia) (14) .…”

The clinical features of OSTM1‐associated malignant infantile osteopetrosis: A retrospective, single‐center experience over one decade

“…The clinical features of published 22 patients with OSTM1 MIOP are summarized in Table2.OSTM1 mutation causes a multi-systemic disease, as the gene is expressed in various tissues including the brain, heart, liver, kidney, and bone(Chalhoub et al, 2003). However, the exact repertoire of OSTM1 functions remains unknown(Ott et al, 2013;Shin et al, 2014;Vacher et al, 2020). The best characterized function is the formation of the OSTM1 beta-subunit and the support of the CLC-7 channel in lysosomes on osteoclasts, which, if absent, interferes with osteoclast secretory function(Lange et al, 2006;Leisle et al, 2011;Mazzolari et al, 2009;Pressey et al, 2010).…”