Pax5-Deficient Mice Exhibit Early Onset Osteopenia with Increased Osteoclast Progenitors

Abstract

Pax5 encodes BSAP, a member of the paired box domain transcription factors, whose expression is restricted to B lymphocyte lineage cells. Pax5−/− mice have a developmental arrest of the B cell lineage at the pro-B cell stage. We show here that Pax5−/− mice are severely osteopenic, missing 60% of their bone mass. The osteopenia can be accounted for by a >100% increase in the number of osteoclasts in bone measured histomorphometrically. This is not due to a lack of B cells, because other strains of B cell-deficient mice do not exhibit this phenotype. There was no difference in the number of osteoclasts produced in vitro by wild-type and Pax5−/− bone marrow cells. In contrast, spleen cells from Pax5−/− mice produce as much as five times the number of osteoclasts as control spleen cells. Culture of Pax5−/− spleen cells yields a population of adherent cells that grow spontaneously in culture without added growth factors for >4 wk. These cells have a monocyte phenotype, produce large numbers of osteoclasts when induced in vitro, and therefore are highly enriched in osteoclast precursors. These data demonstrate a previously unsuspected connection between B cell and osteoclast development and a key role for Pax5 in the control of osteoclast development.

The Paired-box Homeodomain Transcription Factor Pax6 Binds to the Upstream Region of the TRAP Gene Promoter and Suppresses Receptor Activator of NF-κB Ligand (RANKL)-induced Osteoclast Differentiation

“…Consistent with our results (Fig. 1A), however, no expression of Pax5 in osteoclasts and osteoblasts is detected, suggesting an indirect regulatory system (40). Given that bone metabolism is regulated not only by factors intrinsic to osteoblasts and osteoclasts but also by numerous extrinsic factors, the phenotypes observed in Pax5 mutant mice may be caused by regulatory mechanisms extrinsic to osteoblasts and osteoclasts.…”

“…It has been reported that Pax5-deficient mice exhibit osteopenia (25), a pathological condition in which osteoclasts are likely to be involved (39). Although Pax5 was detected only in the B cell lineage, and not in bone marrow macrophages nor in osteoclasts (40), the report nonetheless suggests that Pax5 or its related Pax family members may play a role in bone metabolism. In fact, the findings of a mutation in PAX6 in a human case with Darier disease, aniridia, and bone cysts implicate a possible role for PAX6 in bone remodeling with ATPA2 (30).…”

“…Pax5-deficient mice exhibit early onset osteopenia, with increased osteoclast precursors and delayed osteoblast maturation (40), and Pax5 can modulate bone resorption. Consistent with our results (Fig.…”

The transcription factor paired box-5 promotes osteoblastogenesis through direct induction of Osterix and Osteocalcin

“…Pax5 is shown to be expressed by the pro-B cells to the mature B cells in the hematopoietic system with a role to control the differentiation, function and identity of B lymphocytes, (25,26) whereas a low bone mass phenotype is seen due to the increased osteoclastic parameters, along with normal or slightly decreased osteoblastic parameters on histomorphometric analysis in Pax5 -/-mice. (12) Although neither the proliferative response nor the production of ALP is significantly different between cultured calvarial osteoblasts prepared from WT and Pax5-null mice throughout the culture period; indeed, Pax5 deficiency is shown to increase the number of osteoblastic precursors in bone marrows without affecting the number of mature osteoblasts in bones. (12) These in vivo findings in Pax5-null mice are apparently in disagreement with the present in vitro experimental results in preosteoblastic MC3T3-E1 cells with knockdown by siRNA and stable overexpression of Pax5.…”

“…(9,10) These Pax proteins are shown to play a pivotal role in organogenesis during embryonic development as transcription factors with restricted spatial and temporal expression patterns. (9,10) Although skeletal abnormalities are indeed seen in mice globally deficient of particular Pax proteins, including Pax1, (11) Pax5, (12) Pax7, (13) and Pax9, (14) little attention has been paid to a role of Pax family members in osteoblastogenesis. In the present study, therefore, we have attempted to show the possible involvement of the Pax family members in mechanisms underlying the regulation of osteoblastogenesis for bone formation and remodeling, using in vitro and in vivo experimental techniques.…”