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The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.

CXCR4 regulates hematopoietic and tumor cell homing to bone, but its role during osteoclast (OC) development is unknown. We investigated the role of CXCR4 in osteoclastogenesis and in a model of bone metastasis. Compared with controls, mice reconstituted with CXCR4 null hematopoietic cells exhibited elevated markers of bone resorption, increased OC perimeter along bone, and increased bone loss. CXCR4-/- OCs demonstrated accelerated differentiation and enhanced bone resorption in vitro. Furthermore, tumor growth specifically in bone was significantly increased in mice reconstituted with CXCR4-/- hematopoietic cells. Finally, enhancement of bone tumor growth in the absence of CXCR4 was abrogated with the OC inhibitor, zoledronic acid. These data demonstrate that disruption of CXCR4 enhances osteoclastogenesis and suggest that inhibition of CXCR4 may enhance established skeletal tumor burden by increasing OC activity.

The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf(-/-) mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf(-/-) mice had increased expression of OB genes while Arf(-/-) OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf(-/-) mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf(-/-) tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf(+/-) mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf(-/-) mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS.

The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12/ OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not [P2ry12.sup.-/-], OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP 1) activation and subsequent [α.sub.IIb][β.sub.3] integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin [β.sub.3] gene knockout ([Itgb3.sup.-/-]) OCs, but its effects were substantially blunted in [P2ry12.sup.-/-] OCs. In vivo, [P2ry12.sup.-/-] mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.

This study aimed to determine if there is an association between ABO blood type and severity of COVID-19 defined by intubation or death as well as ascertain if there is variability in testing positive for COVID-19 between blood types. In a multi-institutional study, all adult patients who tested positive for COVID-19 across five hospitals were identified and included from March 6th to April 16th, 2020. Hospitalization, intubation, and death were evaluated for association with blood type. Univariate analysis was conducted using standard techniques and logistic regression was used to determine the independent effect of blood type on intubation and/or death and positive testing. During the study period, there were 7648 patients who received COVID-19 testing throughout the institutions. Of these, 1289 tested positive with a known blood type. A total of 484 (37.5%) were admitted to hospital, 123 (9.5%) were admitted to the ICU, 108 (8.4%) were intubated, 3 (0.2%) required ECMO, and 89 (6.9%) died. Of the 1289 patients who tested positive, 440 (34.2%) were blood type A, 201 (15.6%) were blood type B, 61 (4.7%) were blood type AB, and 587 (45.5%) were blood type O. On univariate analysis, there was no association between blood type and any of the peak inflammatory markers (peak WBC, p = 0.25; peak LDH, p = 0.40; peak ESR, p = 0.16; peak CRP, p = 0.14) nor between blood type and any of the clinical outcomes of severity (admission p = 0.20, ICU admission p = 0.94, intubation p = 0.93, proning while intubated p = 0.58, ECMO p = 0.09, and death p = 0.49). After multivariable analysis, blood type was not independently associated with risk of intubation or death (referent blood type A; blood type B: AOR: 0.72, 95% CI: 0.42–1.26, blood type AB: AOR: 0.78, CI: 0.33–1.87, blood type O: AOR: 0.77, CI: 0.51–1.16), rhesus factor positive (Rh+): AOR: 1.03, CI: 0.93–1.86. Blood type A had no correlation with positive testing (AOR: 1.00, CI: 0.88–1.13), blood type B was associated with higher odds of testing positive for disease (AOR: 1.28, CI: 1.08–1.52), AB was also associated with higher odds of testing positive (AOR: 1.37, CI: 1.02–1.83), and O was associated with a lower risk of testing positive (AOR: 0.84, CI: 0.75–0.95). Rh+ status was associated with higher odds of testing positive (AOR: 1.23, CI: 1.003–1.50). Blood type was not associated with risk of intubation or death in patients with COVID-19. Patients with blood types B and AB who received a test were more likely to test positive and blood type O was less likely to test positive. Rh+ patients were more likely to test positive.

In this trial we studied the effect of pamidronate on periprosthetic bone turnover and pelvic implant migration over 2 years after hybrid total hip arthroplasty (THA). Twenty-two patients received 90 mg of pamidronate and 22 received placebo at randomization 5 days after surgery. Rapid periprosthetic bone loss occurred in the placebo group over the first 6 months and was accompanied by transient increases in biochemical markers of bone turnover. Partial recovery in bone mass occurred in most regions after this period. No recovery of bone mass occurred at the femoral calcar or the medial wall of the acetabulum. Femoral calcar bone loss at 2 years was strongly predicted by acute biomarker changes at week 6. Pamidronate therapy reduced femoral bone loss in the region of the femoral calcar ( P=0.01), but did not affect pelvic bone loss. Pamidronate therapy also inhibited the transient rise in biochemical markers of bone turnover during this period. Pamidronate therapy did not affect acetabular cup migration. Cup migration was inversely related to subject age, but unrelated to initial post-operative bone mineral density, or subsequent bone loss. In summary, early periprosthetic bone loss is associated with a transient expansion of the bone remodeling space. Bisphosphonate therapy reduces femoral calcar bone loss and bone turnover after THA, but did not influence cup migration in this study. Acute changes in biochemical markers predict femoral periprosthetic bone loss.